Search Results (254)

Herpes simplex virus type 1 (HSV-1) is a leading cause of infectious corneal blindness worldwide. Human donor corneal transplantation remains the primary treatment for scarred corneas resulting from herpes simplex keratitis (HSK), a severe inflammatory corneal disease caused by HSV-1 infection, despite a high risk of re-infection or immune rejection of the allografts. As possible alternatives to donor grafting for HSK, we developed cell-free, regeneration-stimulating corneal implants designed to work even under adverse inflammatory situations such as severe infections. The implants comprised short, fully synthetic collagen-like peptides conjugated to polyethylene glycol (CLP-PEG) and crosslinked using carbodiimide chemistry. Being cell-free, they lacked the cellular targets that an already activated immune system would encounter in these inflamed corneas. We tested the performance of these implants in guinea pig and rabbit models of HSK. Three different HSV-1 strains were used to create experimental HSK in rabbits and guinea pigs. There were no overall statistically significant species differences or species–strain differences in virus-induced mortality. At three months post-operation, all treated corneas showed tissue regeneration, but with haze or neovascularization. The initially cell-free CLP-PEG implants allowed for repopulation by ingrowing cells to regenerate neocorneal tissue, despite the inflammation. However, they did not prevent HSV-1 reactivation nor re-infection, as neovascularization and disorganization were observed within the neocorneas. A detailed histopathological examination revealed viral strain differences, but only KOS infection showed interspecies neovascularization differences. A more detailed examination with larger numbers of animals is merited to fully elucidate the effects of the different viral strains on rabbits versus guinea pigs. Full article

Target tracking in typical radar applications faces critical challenges in complex environments, including nonlinear dynamics, non-Gaussian noise, and sensor outliers. Current robustness-enhanced approaches remain constrained by empirical kernel tuning and computational trade-offs, failing to achieve balanced noise suppression and real-time efficiency. To address these limitations, this paper proposes the variational Bayesian-based maximum correntropy criterion cubature Kalman filter (VBMCC-CKF), which integrates variational Bayesian inference with CKF to establish a fully adaptive robust filtering framework for nonlinear systems. The core innovation lies in constructing a joint estimation framework of state and kernel size, where the kernel size is modeled as an inverse-gamma distributed random variable. Leveraging the conjugate properties of Gaussian-inverse gamma distributions, the method synchronously optimizes the state posterior distribution and kernel size parameters via variational Bayesian inference, eliminating reliance on manual empirical adjustments inherent to conventional correntropy-based filters. Simulation confirms the robust performance of the VBMCC-CKF framework in both single and multi-target tracking under non-Gaussian noise conditions. For the single-target case, it achieves a reduction in trajectory average root mean square error (Avg-RMSE) by at least 14.33% compared to benchmark methods while maintaining real-time computational efficiency. Integrated with multi-Bernoulli filtering, the method achieves a 40% lower optimal subpattern assignment (OSPA) distance even under 10-fold covariance mutations, accompanied by superior hit rates (HRs) and minimal trajectory position RMSEs in cluttered environments. These results substantiate its precision and adaptability for dynamic tracking scenarios. Full article

Background/Objectives: Vitamin D (VD) is a fat-soluble vitamin essential for bone health, and calcium and phosphorus absorption. Recently, new interesting functions are reported such as neuroprotective activity, regulatory roles in the immune system, and protective effects in cancer patients. However, the lipophilic nature of VD represents a limitation, as it is associated with low solubility and poor absorption; additionally, VD exhibits poor stability. Methods: Two nanoliposomes containing VD, conventional (LP-VD) and conjugated with D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS, LPT-VD), were developed. The physical and chemical stability during the storage and gastrointestinal stability, the dissolution profile, the cytotoxicity and the Caco-2 cellular uptake were investigated. Nanoliposomes were fully characterized determining sizes, PdI, Zeta potential, encapsulation efficiency and recovery and they were lyophilized to improve stability. Subsequently, the freeze-dried liposomes were encapsulated in hard gelatin capsules to mimic an oral dosage form, and they were subjected to dissolution test. Results: LP-VD exhibited an average size of 85.50 ± 5.70 nm, a PdI of 0.24 ± 0.06, and a ZP of −20.90 ± 4.37 mV. LPT-VD showed an average size of 61.70 ± 3.90 nm, a PdI of 0.26 ± 0.02, and a ZP of −9.45 ± 2.99 mV. The EE% values were 95.76 ± 1.26% and 97.54 ± 3.24% for LP-VD and LPT-VD, respectively. Both nanoliposomes solubilized 2 mg/mL of VD and improved both its storage stability and stability in aqueous and gastrointestinal environment. The freeze-dried products guarantee constant chemical-physical parameters for 28 days at 25 °C. VD dissolution profile was improved. Conclusions: Nanoliposomes, in particular LPT-VD, showed the best results in terms of chemical stability, dissolution profile, and Caco-2 cellular uptake, confirming the stabilization, bioenhancer properties and P-gp inhibition capabilities of TPGS. Full article

We report the exceptional observations of amplified eastward subauroral polarization streams (SAPS) made by the F15 spacecraft at ~840 km altitude near magnetic midnight during 2015–2016 in 17 events. The results show the dawn-cell-associated amplified eastward SAPS flows streaming alongside the duskward-extending dawn cell. The amplified eastward SAPS flows maximized at ~3200 m/s within their respective deep plasma density troughs, mimicking the SAPS flows and thus implying positive feedback mechanisms in action, where the electron temperature reached ~7000 K. One set of correlated magnetosphere–ionosphere conjugate observations is also presented. This illustrates the magnetotail-reconnection-related inward-directed cross-tail convection electric field (E_C) reaching the near-earth plasmasheet’s tailward end, while the inward-directed SAPS E field was absent on the inner-magnetosphere plasmapause, and the emerging eastward SAPS flow in the conjugate ionosphere. These results provide observational evidence that the earthward-propagating inward-directed dawn–dusk cross-tail E field (1) mapped down to auroral latitudes with an equatorward direction, (2) propagated to subauroral latitudes, and (3) played a key role in the development of the emerging eastward SAPS flow and in the amplification of the fully-developed eastward SAPS flows near magnetic midnight, while positive feedback mechanisms supported further SAPS growth. Full article

Chemiresistive gas sensors are extensively employed in environmental monitoring, disease diagnostics, and industrial safety due to their high sensitivity, low cost, and miniaturization. However, the high cross-sensitivity and poor selectivity of gas sensors limit their practical applications in complex environmental detection. In particular, the mechanisms underlying the selective response of certain chemiresistive materials to specific gases are not yet fully understood. In this review, we systematically discuss material design strategies and system integration techniques for enhancing the selectivity and sensitivity of gas sensors. The focus of material design primarily on the modification and optimization of advanced functional materials, including semiconductor metal oxides (SMOs), metallic/alloy systems, conjugated polymers (CPs), and two-dimensional nanomaterials. This study offers a comprehensive investigation into the underlying mechanisms for enhancing the gas sensing performance through oxygen vacancy modulation, single-atom catalysis, and heterojunction engineering. Furthermore, we explore the potential of emerging technologies, such as bionics and artificial intelligence, to synergistically integrate with functional sensitive materials, thereby achieving a significant enhancement in the selectivity of gas sensors. This review concludes by offering recommendations aimed at improving the selectivity of gas sensors, along with suggesting potential avenues for future research and development. Full article

We develop a rigorous algebraic–analytic framework for multidual complex numbers ${\mathbb{DC}}_n$ within the setting of Clifford analysis and establish a comprehensive theory of hyperholomorphic multidual complex-valued functions. Our main contributions are (i) a fully coupled multidual Cauchy–Riemann system derived from the Dirac operator, yielding precise differentiability criteria; (ii) generalized conjugation laws and the associated norms that clarify metric and geometric structure; and (iii) explicit operator and kernel constructions—including generalized Cauchy kernels and Borel–Pompeiu-type formulas—that produce new representation theorems and regularity results. We further provide matrix–exponential and functional calculus representations tailored to ${\mathbb{DC}}_n$, which unify algebraic and analytic viewpoints and facilitate computation. The theory is illustrated through a portfolio of examples (polynomials, rational maps on invertible sets, exponentials, and compositions) and a solvable multidual boundary value problem. Connections to applications are made explicit via higher-order automatic differentiation (using nilpotent infinitesimals) and links to kinematics and screw theory, highlighting how multidual analysis expands classical holomorphic paradigms to richer, nilpotent-augmented coordinate systems. Our results refine and extend prior work on dual/multidual numbers and situate multidual hyperholomorphicity within modern Clifford analysis. We close with a concise summary of notation and a set of concrete open problems to guide further development. Full article

Antibody–drug conjugates (ADCs) are a rapidly advancing class of targeted cancer therapeutics that couple the antigen specificity of monoclonal antibodies (mAbs) with the potent cytotoxicity of small-molecule drugs. In their core design, a tumor-targeting antibody is covalently linked to a cytotoxic payload via a chemical linker, enabling the selective delivery of highly potent agents to malignant cells while sparing normal tissues, thereby improving the therapeutic index. Humanized and fully human immunoglobulin G1(IgG1) antibodies are the most common ADC backbones due to their stability in systemic circulation, robust Fcγ receptor engagement for immune effector functions, and reduced immunogenicity. Antibody selection requires balancing tumor specificity, internalization rate, and binding affinity to avoid barriers to tissue penetration, such as the binding-site barrier effect, while emerging designs exploit tumor-specific antigen variants or unique post-translational modifications to further enhance selectivity. Advances in antibody engineering, linker chemistry, and payload innovation have reinforced the clinical success of ADCs, with more than a dozen agents FDA approved for hematologic malignancies and solid tumors and over 200 in active clinical trials. This review critically examines established and emerging conjugation strategies, including lysine- and cysteine-based chemistries, enzymatic tagging, glycan remodeling, non-canonical amino acid incorporation, and affinity peptide-mediated methods, and discusses how conjugation site, drug-to-antibody ratio (DAR) control, and linker stability influence pharmacokinetics, efficacy, and safety. Innovations in site-specific conjugation have improved ADC homogeneity, stability, and clinical predictability, though challenges in large-scale manufacturing and regulatory harmonization remain. Furthermore, novel ADC architectures such as bispecific ADCs, conditionally active (probody) ADCs, immune-stimulating ADCs, protein-degrader ADCs, and dual-payload designs are being developed to address tumor heterogeneity, drug resistance, and off-target toxicity. By integrating mechanistic insights, preclinical and clinical data, and recent technological advances, this work highlights current progress and future directions for next-generation ADCs aimed at achieving superior efficacy, safety, and patient outcomes, especially in treating refractory cancers. Full article

DprA (also known as Smf) is a conserved RecA mediator originally characterized by its role in natural chromosomal transformation, yet its widespread presence across bacteria hints at broader DNA metabolic functions. Here, we demonstrate that Bacillus subtilis DprA enhances the frequency of Escherichia coli Hfr conjugation in vivo. In vitro, RecA·ATP binds and cooperatively polymerizes in a 50-nucleotide (nt) polydeoxy T (dT)₅₀ ssDNA to form dynamic filaments that SSB inhibits, an effect fully reversed by Bacillus subtilis DprA. Escherichia coli RecA bound to (dT)₂₁ exhibits minimal dATPase activity, but the addition of B. subtilis DprA significantly stimulates RecA dATP hydrolysis. B. subtilis RecA·dATP readily assembles on (dT)₂₀ complexes, and DprA allosterically activates RecA on even shorter (dT)₁₅ substrates. Combining biochemical assays with a fully atomic model of the RecA–DprA–ssDNA complex, we proposed that only one DNA binding site of the DprA dimer engages the ssDNA during RecA loading, owing to steric constraints. This work refines the mechanism of DprA-mediated RecA nucleation and defines the minimal ssDNA footprint required for mediator activity. Full article

Objectives: A thorough understanding of pharmacokinetics and metabolism is critical during early drug development. This study investigates the absorption, distribution, metabolism, and excretion (ADME) profile of R14, a novel compound, using a combination of in vitro and in vivo approaches. Methods: In vitro studies included Caco-2 permeability assays, metabolic stability evaluations in liver microsomes and hepatocytes, and identification of CYP isoforms responsible for R14 metabolism. In vivo pharmacokinetic and metabolic profiling was conducted in rats following oral administration. R14 was quantified using UHPLC-MS/MS. Metabolites were identified using high-resolution UHPLC- QTOF MS/MS, and relative exposure was estimated using peak area-derived AUCs. Results: R14 exhibited low oral bioavailability (13.4%) and high systemic clearance (2.63 L/h/kg), indicating high hepatic extraction. A total of 21 plasma and 38 urine metabolites were identified. Major metabolic pathways included initial hydroxylation and hydrogenation, followed by sequential methylation and Phase II conjugations (glucuronidation and sulfation). Key metabolites (M3, M4, M22, M38) accounted for the majority of systemic exposure. Less than 1% of the unchanged drug was excreted in urine, confirming extensive metabolism. Notably, discrepancies between in vitro and in vivo metabolite profiles suggested rapid further transformation of initial metabolites in vivo, which were not fully captured in vitro. Conclusions: This study demonstrates an efficient and integrated strategy for early-phase ADME characterization. The combined use of in vitro assays and in vivo studies, guided by advanced analytical techniques, provides a robust framework for understanding drug metabolism. These findings can inform drug optimization and help minimize risks in later stages of development. Full article

Background/Objectives: Temozolomide is an important drug used for the treatment of glioblastoma multiforme. Covalent conjugation of temozolomide to triplex-forming oligonucleotides could facilitate better sequence discrimination when targeted to DNA to lessen off-target effects and potentially reduce side-effects associated with conventional chemotherapy. The base sensitivity of temozolomide precludes use of basic deprotection conditions that typify the solid-supported synthesis of oligonucleotides. Methods: A novel di-iso-propylsilylene-linked solid support was developed and used in solid-supported synthesis of oligonucleotide conjugates. Results: Conditions were established whereby fully deprotected, solid-supported oligonucleotides could be prepared for derivatisation. Cleavage of the di-iso-propylsilylene linker was possible using mild, acidic conditions. Conclusions: The di-iso-propylsilylene-linked solid support was developed and shown to be compatible with base-sensitive oligonucleotide conjugate formation. The DNA triplex formation exhibited by a temozolomide oligonucleotide conjugate was equal in stability to the unconjugated control, opening new possibilities for sequence selective delivery of temozolomide to targeted DNA. Full article

The intelligently thermosensitive 2-methacryloyloxyethyl phosphorylcholine (MPC) groups-conjugated methylcellulose (MC) hydrogel, abbreviated as MPC-g-MC, exhibits good potential for prevention of postoperative adhesions. However, its thermosensitive gelation mechanism and why the MPC-g-MC hydrogel shows a lower gelation temperature than that of MC hydrogel are still unclear. Molecular dynamics (MD) simulation was thus used to investigate these mechanisms in this work. After a fully atomistic MPC-g-MC molecular model was constructed, MD simulations during the thermal simulation process and at constant temperatures were performed using GROMACS 2022.3 software. The results indicated that the hydrophobic interactions between the MPC-g-MC molecular chains increased, the interactions between the MPC-g-MC molecular chains and H₂O molecules decreased with the rise in temperature, and the hydrogen bonding structures were changed during the thermal simulation process. As a result, the MPC-g-MC molecular chains began to aggregate at about 33 °C (close to the gelation temperature of 33 °C determined by the rheological measurement), bringing about the formation of the MPC-g-MC hydrogel in the macroscopic state. The mechanism of MPC-g-MC hydrogel formation showed that its lower gelation temperature than that of the MC hydrogel is attributed to the increase in the interactions (including hydrophobic interactions, hydrogen bonding interactions, Van der Waals and Coulomb forces) induced by the side MPC groups of MPC-g-MC molecules. The thermosensitive gelation mechanism revealed in this study provides an important reference for the development of novel thermosensitive MC-derived hydrogels with gelation temperatures close to human body temperature. Full article

Citrus fruits are major economic and nutritional crops that are sometimes subjected to serious attacks by many fungal phytopathogens after harvesting. In this study, we focus on the structures of potential antifungal nanocomposites from artichoke leaf extract (Art), Art-mediated nanosilver (AgNPs), and their nanoconjugates with chitosan nanoparticles (Cht) to eradicate the blue mold fungus (Penicillium italicum) and preserve oranges during storage via nanocomposite-based edible coatings (ECs). The biosynthesis and conjugation of nanomaterials were verified using UV and infrared (FTIR) spectroscopy, electron microscopy (TEM and SEM) analysis, and DLS assessments. Art could effectually biosynthesize/cap AgNPs with a mean size of 10.35 nm, whereas the average size of Cht was 148.67 nm, and the particles of their nanocomposites had average diameters of 203.22 nm. All nanomaterials/composites exhibited potent antifungal action toward P. italicum isolates; the Cht/Art/AgNP nanocomposite was the most effectual, with an inhibition zone of 31.1 mm and a fungicidal concentration of 17.5 mg/mL, significantly exceeding the activity of other compounds and the fungicide Enilconazole (24.8 mm and 25.0 mg/mL, respectively). The microscopic imaging of P. italicum mycelia treated with Cht/Art/AgNP nanocomposites emphasized their action for the complete destruction of mycelia within 24 h. The orange (Citrus sinensis) fruit coatings, with nanomaterial-based ECs, were highly effectual for preventing blue mold development and preserved fruits for >14 days without any infestation signs; when the control infected fruits were fully covered with blue mold, the infestation remarks covered 12.4%, 5.2%, and 0% of the orange coated with Cht Art/AgNPs and Cht/Art/AgNPs. The constructed Cht/Art/AgNP nanocomposites have potential as effectual biomaterials for protecting citrus fruits from fungal deterioration and preserving their quality. Full article

Cyanobacteria-derived peptides represent a promising class of anticancer agents due to their structural diversity and potent bioactivity. They exert cytotoxic effects through mechanisms including microtubule disruption, histone deacetylase inhibition, and apoptosis induction. Several peptides—most notably the dolastatin-derived auristatins—have achieved clinical success as cytotoxic payloads in antibody–drug conjugates (ADCs). However, challenges such as limited tumor selectivity, systemic toxicity, and production scalability remain barriers to broader application. Recent advances in targeted delivery technologies, combination therapy strategies, synthetic biology, and genome mining offer promising solutions. Emerging data from preclinical and clinical studies highlight their therapeutic potential, particularly in treatment-resistant cancers. In this review, we (i) summarize key cyanobacterial peptides and their molecular mechanisms of action, (ii) examine progress toward clinical translation, and (iii) explore biotechnological approaches enabling sustainable production and structural diversification. We also discuss future directions for enhancing specificity and the therapeutic index to fully exploit the potential of these marine-derived peptides in oncology. Full article

Photodynamic therapy (PDT) is a minimally invasive technique—used for the local eradication of neoplastic cells—that exploits the interaction of light, oxygen, and a photo-responsive drug called photosensitizer (PS) for the local generation of lethal ROS. Push-pull chromophores, that bear electron donor (D) and acceptor (A) groups linked through a π-electron bridge, are characterized by a non-homogeneous charge distribution in their excited state, with charge transfer from one extremity of the chain to the other one (Internal Charge Transfer—ICT). This phenomenon has a direct impact on the photophysical features of the push-pull compounds, as the bathochromic shift of the emission maxima and intersystem crossing (ISC) of the excited state are directly connected with the production of reactive oxygen species (ROS). In continuing our research regarding the synthesis and use of oligophenylene ethynylenes (OPEs) in PDT, two new push-pull glycosyl OPE-NOF and OPE-ONF—featuring electron-donor N,N-dimethylamino (N) and dimetoxyaryl (O) and acceptor tetrafluoroaryl (F) moieties on the OPE chain—have been efficiently prepared. The interchanged position of the D groups onto the conjugated skeleton was aimed to tune and optimize the push-pull effect, while the introduction of glucoside terminations was directed to give biocompatibility and bioaffinity to the chromophores. OPE-NOF, OPE-ONF, and the synthetic intermediates were fully characterized, and their photophysical properties were investigated by using UV-Vis absorption and emission spectroscopy. OPE-NOF showed a strong charge-transfer character and high PDT effect on HeLa cancer cells when irradiated with non-harmful blue light, causing massive cancer cell death. Full article

Nitrogen-containing substitutes, such as 1,2,3-triazoles and Mannich bases, are major pharmacophore systems, among others. The presented review summarizes the recent advances (2019–2024) in the synthesis of 1,2,3-triazoles and Mannich bases conjugated with a triterpenic core. These structural modifications have proven to be effective strategies for modulating the biological activity of triterpenes, with particular emphasis on antitumor and antiviral properties. Recent efforts in expanding the structural diversity of triazoles through A-ring modifications and C28 (or C30) substitutions are discussed. Notably, the first examples of N-alkylation of indole triterpenoids by propargyl bromide are presented, along with the application of propargylamine in the synthesis of rare triterpenic aldimines. The review also covers an application of triterpene alkynes in Mannich base synthesis, focusing on functionalization at various positions, including C28 and C19 of the lupane platform, and incorporating of amino acid spacers. While significant progress has been made both in synthetic strategies and pharmacological applications, further research is needed to fully explore the antibacterial, anti-inflammatory, and antidiabetic potential. The review will be useful to researchers in the fields of organic synthesis, natural product and medicinal chemistry, and pharmacology. Full article