Search Results (226)

Aspergillus fumigatus is a leading cause of invasive fungal disease in humans and is classified as a critical priority threat by the World Health Organization. Triazole antifungals remain the cornerstone of therapy, yet their effectiveness is steadily being eroded by the continuous rise in drug resistance. Most resistance mechanisms trace back to mutations in Cyp51A, spawning well-defined genotypes such as TR₃₄/L98H and TR₄₆/Y121F/T289A. However, the Cyp51A genotype–phenotype landscape in A. fumigatus is far from straightforward. Isolates that share an identical TR genotype can display strikingly divergent susceptibility profiles, and mutational hotspots in Cyp51A, such as G54, M220 and G448, are linked to varying resistances, challenging assumptions about predictable resistance behavior. Complicating matters further, an expanding array of resistance mechanisms, independent of Cyp51A, is now being uncovered. This review summarizes the current state of knowledge on azole resistance in A. fumigatus, dissecting the intricate genotype–phenotype relationships, spotlighting emerging non-Cyp51A pathways and outlining future strategies to enhance the detection and clinical management of antifungal resistance. Full article

As an effective approach to boosting consumption and facilitating the recycling of consumer goods, trade-in programs have been widely adopted by branders and e-commerce platforms. A platform supply chain system comprising e-commerce platforms and branders is investigated in this paper for this purpose. We construct a two-stage dynamic game model encompassing eight scenarios, discussing the provision of trade-in programs and product recycling issues under the resale and agency selling modes. Below are the key findings: (1) Trade-In Programs: In the resale mode, both branders and platforms prefer to adopt self-recycling when market potential is large, while opting for recycling undertaken by the other party when market potential is small. In the agency selling mode, branders prefer to adopt self-recycling (B-II) when fixed costs are high and the salvage value of used products is high, while platforms choose platform-led recycling (P-II) when fixed costs are low and the salvage value of used products is high. (2) Product Recycling: In the resale mode, branders should opt for self-recycling when facing high fixed costs, small market potential, and high salvage values, while outsourcing is more appropriate when salvage values are low. When the market potential is low, the platform ought to prefer self-recycling if the salvage value is either sufficiently high or sufficiently low; otherwise, outsourcing is preferable. In the agency selling mode, when the salvage value of used products is relatively high, platforms tend to have a free-riding mentality. When platforms provide trade-in programs, they will prioritize self-recycling if the salvage value is higher. In contrast, branders consistently achieve maximum profits when platforms adopt self-recycling. (3) Selection of Selling Mode: Branders always prefer the agency selling mode, while platforms’ mode selection depends on the trade-off between salvage value and commission rate. This study provides strategic insights for platform-based supply chain decisions. Full article

Background: Piperine, an alkaloid from Piper nigrum, modulates oxidative stress, proliferation, and survival pathways in several cancer models; however, its mechanistic effects in colorectal epithelial Caco-2 cells remain insufficiently defined. Objective: This study aimed to investigate the cytotoxic, antiproliferative, oxidative, autophagic, and anti-migratory effects of piperine in Caco-2 cells. Methods: Caco-2 cells were treated with piperine (0.001–0.1 mg/mL) for up to 72 h. Cell viability, proliferation, and migration were assessed using SRB and scratch assays. Oxidative stress, apoptosis, autophagy, and tight junction integrity were evaluated through ROS quantification, Western blotting, gene expression analysis, confocal microscopy, and transmission electron microscopy (TEM). NACET was used to determine the contribution of oxidative stress to piperine-induced cytotoxicity and autophagy. Results: Piperine induced a time- and dose-dependent reduction in viability, with viability decreasing to 53.0 ± 2.88% at 0.1 mg/mL after 72 h. Proliferation decreased to 51% of control levels (p < 0.001), accompanied by p21 upregulation (p < 0.05), indicating G2/M cell cycle arrest. Piperine markedly increased intracellular ROS (p < 0.001), downregulated NRF2 (p < 0.05), and suppressed GSTA1 expression (p < 0.001), while NACET co-treatment restored viability (p < 0.001). No activation of caspase-dependent apoptosis was observed. Piperine significantly enhanced autophagic flux, as shown by the increased LC3B-II/LC3B-I ratio (p < 0.01), elevated LC3B-II/LAMP-1 co-localization (p < 0.01), and chloroquine-induced accumulation of LC3B-II and p62 (p < 0.01), with preserved lysosomal function. TEM analysis confirmed a marked increase in double-membrane autophagosomes in piperine-treated cells compared with controls. NACET reduced LC3B-II/LC3B-I levels, increased p21 expression, and significantly improved cell viability, indicating that piperine-induced autophagy is cytotoxic and driven by oxidative stress. Additionally, piperine upregulated occludin (p < 0.01) and reduced cell migration independently of proliferation (p < 0.01). Conclusions: Piperine exerts antiproliferative effects in Caco-2 cells through ROS-mediated stress, p21-dependent G2/M arrest, and activation of cytotoxic autophagy. Its ability to impair migration and enhance tight junction integrity further supports its potential as a complementary therapeutic agent in colon cancer. Full article

We report a rare family of pyridine-coordinated iodobismuthate(III) salts supported by alkyltriphenylphosphonium and tetraphenylphosphonium cations. Reactions of BiI₃ with Ph₃PR⁺I⁻ (R = Me, Et, ⁿPr, ⁿBu, Ph) in neat pyridine, followed by crystallization, yield structurally tunable bismuth-halide-pyridine anions dictated by reagent stoichiometry. Combination of BiI₃ and Ph₃PR⁺I⁻ in 2:1 ratio produced [Ph₃PR]₂[BiI₅Py], 1 (R = Me, Et, ⁿPr, Ph), while combination in 1:1 ratio resulted in three compounds: [Ph₃PR][cis-BiI₄Py₂], 2 (R = ⁿPr, Ph), [Ph₃PR][trans-BiI₄Py₂], 3 (R = Me, Et, Ph), and [Ph₃PR]₂[transoid-Bi₂I₈Py₂], 4 (R = Me, Et, ⁿPr, ⁿBu, Ph). In many cases, the compounds were isolated as Py or Et₂O solvates, and in some cases, multiple degrees of solvation or polymorphism were encountered. Hirshfeld analysis of 1–4 showed the major anion–cation/anion/solvent interactions to be H⋯I, H⋯H, and C⋯H. Diffuse reflectance measurements of representative compounds, all of which were yellow-orange to red-orange, revealed bandgaps in the range of 1.9–2.2 eV, where density-of-states KS-DFT calculations attribute the absorption to metal-centered charge transfer within the anionic unit. NLMO and QTAIM analyses further indicate predominantly ionic Bi(III)–I/pyridine bonding with robust inner-sphere coordination that is insensitive to anion speciation. Full article

Herpes simplex virus type 1 (HSV-1) is a neurotropic alphaherpesvirus that interacts dynamically with host cells within structured tissue environments. Conventional two-dimensional (2D) cultures do not fully recapitulate these spatial and microenvironmental features. In this study, we established a three-dimensional (3D) culture system using the self-assembling peptide RADA16-I to generate an extracellular matrix–mimetic hydrogel scaffold. This platform supported the formation of stable Vero cell spheroids that remained viable for more than 30 days. Following HSV-1 infection, viral spread initiated at the spheroid periphery and progressively extended toward the core. Sustained viral replication was detected for up to 22 days, indicating long-term maintenance of infection within the 3D structure. Ultrastructural examination identified viral particles and vesicular compartments consistent with autophagy-related organelles. Comparative analysis of autophagy-associated markers revealed distinct temporal patterns between 2D monolayer cultures and 3D spheroids. In the 3D system, LC3B-II levels progressively increased, accompanied by a reduction in p62, suggesting altered regulation of autophagic flux relative to conventional 2D conditions. These findings demonstrate that the RADA16-I-based 3D culture model supports prolonged HSV-1 infection and reproduces key spatial features of viral dissemination. The differential autophagic responses observed between 2D and 3D systems highlight the influence of cellular architecture on host–virus interactions and support the application of 3D culture platforms for mechanistic studies of HSV-1 pathogenesis. Full article

Mastitis is a prevalent disease in the dairy cattle industry and has adverse effects on dairy cows’ health and milk quality. Importantly, mastitis is associated with the inflammatory response and mitophagy. As a complement-regulatory factor, C4b-binding protein alpha (C4BPA) has been shown to modulate inflammatory factors. This study further investigates its role and mechanisms in regulating mitophagy and inflammatory responses. Following C4BPA knockout, bovine mammary epithelial cells (BMECs) exhibited reduced expression of TLR4 and key pro-inflammatory cytokines, namely the tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6). Electron microscopy revealed a marked increase in mitochondrial membrane rupture, as well as cristae disorder and damage and increased reactive oxygen species (ROS) levels. Moreover, Pink1 and Parkin protein levels were increased, as was LC3B lipidation (LC3B-II), whereas p62 protein expression was significantly downregulated. Immunofluorescence indicated substantially increased LC3 colocalization with mitochondria, suggesting that C4BPA gene knockout activated Pink1/Parkin-mediated mitophagy. The fact that C4BPA knockout decreased the levels of p-IκB and p-p65 while increasing those of IκBα and p65 therefore indicates its regulatory role in the NF-κB-mediated inflammatory response. Together, these findings reveal that C4BPA deficiency in BMECs not only activates Pink1/Parkin-mediated mitophagy but also suppresses the NF-κB-mediated inflammatory response. This study provides novel potential molecular targets for predicting mastitis in dairy cattle. Full article

Terpyridines are well-known ligands in coordination chemistry, are valued for their conformational flexibility and strong metal-binding properties, and are also of interest as fluorophores. This study focused on the synthesis and comprehensive investigation of a new class of bis-oxazolo[5,4-b]pyridine derivatives, designed based on their structural similarity to terpyridines. Four novel compounds, 4a–d, were synthesized by cyclization of amide derivatives of 3-aminopyridin-2(1H)-ones using pyridine-2,6-dicarboxylic acid and its dichloride as key acidic components. Their structures and purity were confirmed by melting point analysis, high-resolution mass spectrometry, and ¹H, ¹³C NMR spectroscopy. Compounds 4a–c exhibit UV absorption at 323–357 nm and intense blue to deep-blue fluorescence (357–474 nm, цi ≈ 0.32–0.84) in chloroform, dichloromethane, and acetonitrile, attributed to p–p* transitions within the conjugated ring system. These findings suggest their potential as phosphors for organic electronics. Computational modeling of 4a–c molecules provided insight into their electronic structures, conformational stability, and predicted optical behavior. The most stable conformers (4a–II, 4b–II, 4c–II′) exhibited a progressive decrease in the HOMO–LUMO gap from 4a to 4c, correlated with the enhancement of photoactivity. Among them, compound 4a stands out as the most promising luminophore, displaying the most intense and narrow luminescence band, owing to its high molecular symmetry and stable emission characteristics. Overall, this study lays the foundation for future studies of bis(oxazolo[5,4-b]pyridine) derivatives in coordination chemistry and optoelectronic materials development. Full article

Implant-based breast reconstruction (IBBR) remains the most common form of post-mastectomy reconstruction worldwide, offering patients a reliable and accessible option to restore breast contour. Advances in surgical technique, biomaterials, and implant technology have driven rapid evolution in the field, with the dual goals of improving aesthetic outcomes and minimizing patient morbidity. The prepectoral plane has been popularized due to the eliminated risk of animation deformity and reduced postoperative pain. Some concerns remain regarding mastectomy flap thickness and long-term oncologic and aesthetic outcomes. Concurrently, nipple-sparing mastectomy has improved aesthetic results and enabled surgeons to move beyond just restoring breast form and improve functional recovery as well, as demonstrated by surgical efforts aimed at restoring nipple–areolar complex (NAC) sensation. Adjunctive use of biologic matrices and synthetic meshes has broadened reconstructive options, while next-generation implants seek to further enhance outcomes. Balanced against these innovations are important oncologic and systemic safety concerns, including breast implant-related cancers and the ongoing debate over breast implant illness (BII). This review highlights eight current “hot topics” in implant-based breast reconstruction: (1) prepectoral reconstruction, (2) nipple-sparing mastectomy, (3) oncoplastic techniques, (4) nipple–areolar complex (NAC) neurotization, (5) biologic matrices and synthetic meshes, (6) next-generation implants, (7) optimizing aesthetic outcomes, and (8) implant-associated cancer and systemic concerns. Together, these areas define the current landscape of innovation, controversy, and future directions in implant-based reconstruction. Full article

The basic helix-loop-helix (bHLH) transcription factor ‘Atoh8’ is involved in the regulation of several developmental processes and pathologies. It regulates organogenesis, reprogramming, stem cell fate determination, and cancer development. However, the mechanisms underlying these observations remain unclear. Unlike many tissue-specific bHLH factors, Atoh8 is ubiquitously expressed during development as well as in adult tissues. In this study, we explored whether Atoh8 modulates basic cellular functions, which may reveal a common mechanism that could explain the diverse observations reported in the literature. Our findings demonstrate that the loss of Atoh8 impairs autophagy. In both primary myoblasts and mouse embryonic stem cells lacking Atoh8, we observed differential expression of LC3B-II, TFEB, and accumulation of p62, indicating impairment of autophagy. Furthermore, mass spectrometric analysis performed on C2C12 and Atoh8 overexpressing C2C12 myoblasts revealed significant alterations in the expression of proteins associated with mitochondrial and lysosomal functions. Finally, Cut&Tag sequencing performed in Atoh8 overexpressing C2C12 cells revealed that Atoh8 binds to multiple genes involved in autophagosome assembly. Overall, this study underscores that Atoh8 is a critical regulator of macroautophagy, and its reduction disrupts the autophagic process, whereas its overexpression results in increased autophagic flux. Full article

Natural products hold immense therapeutic potential, yet they remain underexplored due to challenges in activating or producing them in laboratory settings. Here, we investigate the regulatory capabilities of a new medium-sized Streptomyces Antibiotic Regulator Protein (SARP), Fzm_SARP, in comparison to the well-characterized small SARP, RedD, across 18 diverse actinobacterial strains. In addition to the conserved DNA-binding domains typical of SARP regulators, the medium-sized Fzm_SARP also contains an additional NTPase domain. Our study revealed that 327 of the 422 metabolites (77%) detected in 18 wild-type actinobacterial strains were up-regulated in the SARP over-expressing strains. Among these 422 metabolites, 55% were up-regulated in the two SARP over-expressing strains whereas 15% and 7% were specifically up-regulated in the RedD and Fzm_SARP over-expressing strains, respectively. Interestingly, 244 metabolites not previously detected in the wild-type strains were detected in the two SARP over-expressing strains, resulting in a 58% increase from 422 to 666 metabolites. 36% of these new 244 metabolites were up-regulated in the two SARP over-expressing strains whereas 37% and 27% of these metabolites were specifically up-regulated in the RedD and Fzm_SARP over-expressing strains, respectively. These regulator-specific metabolites also give rise to distinct bioactivity profiles observed for each SARP. Overall, these findings expand our understanding of SARP family regulators and offer valuable insights for future research and applications in microbial biotechnology and secondary metabolite production. Full article

While antiretroviral therapy (ART) has significantly improved the morbidity of HIV infection, ART may contribute to the pathogenesis of HIV associated neurocognitive impairment (HIV-NCI) by interfering with autophagic processes in astrocytes. Autophagy and mitophagy remove unwanted/damaged material and mitochondria from the intracellular environment, respectively. Dysregulated autophagy in astrocytes, abundant CNS cells with crucial homeostatic functions, contributes to many neurodegenerative diseases. Few studies have examined effects of ART on autophagy in astrocytes. We treated primary human astrocytes with a common ART regimen and performed LC3B-II and p62 turnover assays. ART significantly inhibited both LC3B-II and p62 turnover. Since p62, one autophagy receptor that mediates mitophagy, autophagic clearance of mitochondria, turnover was inhibited, we also examined mitophagy. While ART decreased BNIP3L/Nix homodimers, there were no changes in PINK1, Parkin, Mt-CO2, mitochondrial mass, or mitochondria–lysosome colocalization, indicating that ART did not inhibit mitophagy. We show that antiretroviral drugs have distinct effects on autophagic processes in astrocytes, which represents an alteration in their homeostasis, a major function of autophagy. This likely contributes to HIV-NCI. Understanding these impacts is important for improving ART for PWH, who have, by necessity, ongoing ART exposure. It also facilitates development of therapies for HIV-NCI that may include modulation of autophagy. Full article

Zoonotic influenza viruses, including highly pathogenic avian influenza and swine-origin variants, continue to cause sporadic human infections with, in some cases, high case fatality rates and potential for sustained human-to-human transmission. The COVID-19 pandemic underscored both the possibilities of rapid vaccine innovation and the persistent challenges in equitable access and public trust. This paper synthesizes the vaccine-related priorities from the 2024 update of the World Health Organization Public Health Research Agenda for Influenza, integrating evidence from systematic literature reviews commissioned, expert consultations, and analysis of lessons learned from recent health emergencies, to outline a research and policy roadmap for zoonotic and pandemic influenza vaccine preparedness. Key research priorities identified include development of broadly protective animal and human vaccines; improved understanding of correlates of protection; rapid and scalable manufacturing platforms; predictive modelling for strain selection; and targeted communication strategies to strengthen uptake. Experts have considered that implementing these priorities will require One Health integration, sustained investment, harmonized regulatory frameworks, and proactive community engagement to ensure that advances in vaccine science translate into timely, equitable public health protection. Full article

Pleurotus nebrodensis, a rare endemic Sicilian mushroom with notable gastronomic and medicinal value, attracts interest for its potential antioxidant properties, though data on its biological effects in skin models are lacking. This study evaluated the antioxidant activities of several aqueous extracts from wild (1a, 2a, 3a, 1b, 2b, and 3b) and cultivated (CAN1 °F, 3A, 2B(II), and CAN2 °F) P. nebrodensis basidiomes in human keratinocytes (HaCaT cells). Extracts were characterized through DPPH radical scavenging assay, MTT viability assay, and intracellular ROS and mitochondrial SOX quantification by DCFH-DA and MitoSOX Red fluorescence analyses. The methodology specifically included two approaches in keratinocytes: co-treatment of extracts and H₂O₂ to investigate direct scavenger activity, and pre-treatment to assess the preventive activity on oxidative stress modulation. This analysis demonstrated that selected extracts (1b and CAN2 °F) exert a dual action, combining anti-intracellular ROS and anti-mitochondrial SOX preventive effect with a direct free radical scavenging activity in human keratinocytes. In particular, CAN2 °F exerts its activity predominantly through prevention (modulation of cellular defenses), while 1b primarily functions as a direct intracellular ROS and mitochondrial SOX scavenger. Notably, glucan quantification revealed a correlation between β-glucan content and the overall antioxidant activity. These findings provide the first evidence of P. nebrodensis’s anti-ROS and anti-SOX efficacy in human keratinocytes, highlighting its potential as a source of natural bioactives for cosmeceutical and dermatological applications. Full article

The C9ORF72 gene mutation is a major cause of amyotrophic lateral sclerosis (ALS). Disease mechanisms involve both loss of C9ORF72 protein function and toxic effects from hexanucleotide repeat expansions. Although its role in neurons and the immune system is well studied, the impact of C9ORF72 deficiency on skeletal muscle is not yet well understood, despite muscle involvement being a key feature in ALS pathology linked to this mutation. This study examined skeletal muscle from C9ORF72 knockout mice and found a 19.5% reduction in large muscle fibers and altered fiber composition. Ultrastructural analysis revealed mitochondrial abnormalities, including smaller size, pale matrix, and disorganized cristae. Molecular assessments showed increased expression of Atrogin-1, indicating elevated proteasomal degradation, and markers of enhanced autophagy, such as elevated LC3BII/LC3BI ratio, Beclin-1, and reduced p62. Mitochondrial quality control was impaired, with a 3.6-fold increase in PINK1, upregulation of TOM20, reduced Parkin, and decreased PGC-1α, suggesting disrupted mitophagy and mitochondrial biogenesis. These changes led to the accumulation of damaged mitochondria. Overall, the study demonstrates that C9ORF72 is critical for maintaining muscle protein and mitochondrial homeostasis. While C9orf72-haploinsufficiency does not directly compromise muscle strength in mice, it may increase the vulnerability of skeletal muscle in C9ORF72-associated ALS. Full article

In this work, systematic first-principles calculations were performed to investigate the multiband emissions of Bi-doped Y₃Ga(Al)₅O₁₂ phosphors. The predicted emissions of Bi³⁺ show that the violet narrow-band emission can be attributed to the ³P₁–¹S₀ transition of Bi³⁺ at Y sites, and both the metal-to-metal charge transfer (MMCT) of Bi³⁺ at Ga (Al) sites and the luminescence of Bi³⁺ dimers can generate visible emissions. Detailed formation energy calculations subsequently rule out the possibility that the visible emission originates from the MMCT of Bi³⁺ at Ga (Al), as the concentration of Bi_Y is much greater than that of B_Ga (or Bi_Al). To better understand the relationship between the nephelauxetic effect and the coordination environment, the vacuum-referred binding energy (VRBE) model was utilized to determine the energy levels of bismuth ions relative to the vacuum level in different systems and at different sites. The results provide insight into the relationship between the coordination environment and the emission properties of Bi³⁺ and are helpful for analyzing and optimizing the luminescent properties of bismuth-doped garnet-like materials. Full article