Megahertz-rate optical coherence tomography (MHz-OCT) is an optical imaging technology that has attracted considerable attention in clinical practice. Its advantages, such as ultra-high speed, noninvasiveness, and high resolution, endow it with broad application prospects in various clinical fields. However, MHz-OCT systems place high demands on the sampling rate and bandwidth of acquisition and data transmission systems, greatly increasing the system cost. Based on a high-speed k-linear swept laser with the acousto-optic deflector (AOD), this paper proposes a hardware-based down-sampling method. Sweeping a narrowband spectrum and utilizing the linear wavenumber characteristic of the laser enables an equivalent down-sampling of the original interference signal. Deep learning is employed to recover high-resolution images from the down-sampled signals. High-quality imaging results have been successfully achieved at a high sweep speed of 1 MHz while using acquisition and data transmission systems with lower bandwidth and sampling rate. The novel down-sampled OCT system proposed in this paper helps to reduce the cost of MHz-OCT systems in clinical settings and promotes their popularization and application.
Patients with Down Syndrome (DS) are characterized by dysfunction of several organs, including the liver, brain, heart defects, gastrointestinal anomalies, and lethal immune hypersensitivity. A person with DS is also susceptible to various inflammatory diseases, including hepatic autoimmune diseases. The Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) is known to trigger the stimulator of interferon genes (STING) and downstream proinflammatory factors. In this work, we hypothesized that oxidative stress-associated DNA damage triggers activation of the cGAS-STING signaling pathway and promotes liver inflammation in DS. Here, we investigated the role of reactive oxygen species (ROS) associated DNA damage and the cGAS-STING signaling pathway in the pathogenesis of hepatic inflammation in the DS model. Our results showed that DS cells harbor excessive ROS and DNA damage in DS fibroblasts and DS mouse liver. Further, DS cells accumulate micronuclei that likely serve as a source of cytoplasmic DNA to stimulate cGAS-STING activation. In addition, RNA-seq analysis results showed enhanced expression of key type I interferon factors in cGAS-STING pathways in DS liver and inflammatory responses and elevated liver enzymes such as alanine transaminase (ALT) that indicate a hepatocellular liver injury in DS. The results of this study opened the opportunity to connect endogenous DNA damage triggers innate immune response, which may contribute to the upregulation of the cGAS-STING signaling to exacerbate hepatic inflammation in DS.
Propofol is a widely employed intravenous general anesthetic that can induce neurotoxic effects on neurons. Previous research has indicated dysregulation of miR-140-3p in the hippocampal tissues of propofol-treated mice. This research was designed to investigate the function and underlying mechanism of miR-140-3p in propofol-induced neurotoxicity. To simulate propofol-induced neurotoxicity, human SH-SY5Y cells and mice were treated with propofol. Commercial kits were used to measure LDH, MDA, SOD, GSH-Px, and BDNF levels. Cells were transfected with miR-140-3p mimics, inhibitor, or BACE1 overexpression plasmids. Gene expression was assessed by RT-qPCR, cell viability by CCK-8, and apoptosis by flow cytometry. Dual-luciferase and RIP assays confirmed that miR-140-3p targets BACE1. The results confirmed that as the concentration of propofol increased, miR-140-3p levels were progressively downregulated, while BACE1 was correspondingly upregulated. Upregulation of miR-140-3p rescued propofol-treated SH-SY5Y cells from cytotoxicity, as evidenced by enhanced viability, suppressed apoptosis, and ameliorated oxidative stress. Consistently, miR-140-3p overexpression also attenuated propofol-induced neurotoxicity in vivo. Furthermore, BACE1 was confirmed to be a direct target of miR-140-3p through experimental validation, and this post-transcriptional repression was shown to mediate the observed neuroprotection. miR-140-3p attenuates propofol-induced neurotoxicity via BACE1 in vitro and in vivo, providing new insights and a potential biomarker for managing propofol-associated neurotoxicity.
Down syndrome (DS) is associated with immune dysregulation and a broad spectrum of autoimmune diseases; however, autoimmune involvement of the pituitary gland remains poorly characterized. Isolated adrenocorticotropic hormone deficiency (IAD) is a rare cause of secondary adrenal insufficiency, and its relationship to DS-related autoimmunity has not yet been elucidated. We encountered a single case of DS that was complicated by IAD. We describe the clinical course in detail and present immunological findings suggestive of an autoimmune basis for IAD in the context of DS. To experimentally evaluate pituitary-directed autoimmunity, circulating antibodies were analyzed using immunofluorescence staining of mouse pituitary tissue. Immunoglobulin G derived from an individual with DS and IAD specifically showed reactivity toward corticotrophs, as demonstrated by colocalization with ACTH immunostaining. HLA genotyping did not identify alleles previously associated with idiopathic IAD, suggesting a disease mechanism distinct from established genetic susceptibility. The identification of anti-corticotroph antibodies in DS provides the first immunological evidence linking IAD to DS-related autoimmunity. These findings suggest that autoimmune IAD may represent a previously unrecognized component of endocrine polyautoimmunity in DS and underscore the importance of considering pituitary autoimmunity in the endocrine assessment of this population. However, considering that the present findings are derived from a single case, further studies are warranted to confirm their broader applicability.
In inertial confinement fusion experiments at the National Ignition Facility, asymmetries are probed by a variety of neutron diagnostics, including neutron imaging systems, real-time neutron activation diagnostics (RTNADs), and neutron spectrometers. It is often useful to generate synthetic data based on these diagnostics to validate and tune models. However, current methods of doing so using Monte Carlo particle tracing are time-consuming. In this paper, an ultra-fast method is presented for generating synthetic neutron images, RTNAD data, and spectrometry data using line integrals and 3D convolutions. While it does not contain as much physics as particle tracing codes, it is thousands of times faster and produces nearly identical data. This enables analysis techniques that depend on generating large amounts of synthetic data, which will prove very useful for the study of asymmetries going forward.
Narrowband terahertz (THz) emission from periodically poled lithium niobate (PPLN) is typically realized in the d33 (extraordinary, z-axis) geometry due to the large nonlinearity of this tensor element. Here, as an alternative, we instead engage the d22 tensor channel in PPLN and show that ordinarily polarized (y-axis), d22-driven quasi-phase-matched (QPM) emission preserves narrowband THz output while shifting matched resonances to lower frequency (typically f33/f22 ≈ 1.5), thereby providing complementary THz lines from the same device. Furthermore, we use an in situ EO-sampling cross-calibration between the two tensor-selective channels to retrieve the relative spectral intensities of the extraordinary and ordinary emission and extract an effective d22/d33 ratio of 0.11 ± 0.03, in agreement with phonon dispersion models. Despite the weaker nonlinearity, d22 excitation still delivers around 10 kV/cm peak fields for 1 mJ pumping. These results establish d22 as a practical secondary channel for extending spectral coverage and enable polarization-selective narrowband THz spectroscopy in PPLN.
Advanced glycation end products (AGEs) accumulate with aging and metabolic stress and are increasingly implicated in osteoarthritis (OA) pathology. However, how AGEs regulate osteoclast-chondrocyte signaling remains poorly defined. Here, we integrated proteomic and transcriptomic analyses with machine learning to identify molecular networks altered by AGEs in osteoclasts. SIRT1 emerged as a central regulator suppressed following AGE exposure. Loss of SIRT1 deacetylase activity activated the RANKL/RANK signaling pathway and enhanced osteoclast differentiation. Pharmacological inhibition of RAGE or shRNA-mediated gene silencing restored SIRT1 expression, confirming the upstream role of AGE-RAGE signaling. In a co-culture system, AGE-treated osteoclasts accelerated chondrocyte senescence, as evidenced by elevated senescence markers and SASP factors. Findings were validated in vivo, where AGEs aggravated cartilage degeneration, subchondral bone alterations, and chondrocyte senescence in an OA mouse model. Collectively, these results identify an AGE-driven SIRT1/RANKL axis that links osteoclast activation with chondrocyte aging, highlighting a critical pathway contributing to joint deterioration. Targeting this mechanism may offer new therapeutic opportunities for delaying age-related OA progression.
The positive feedback loop between epithelial-mesenchymal transition (EMT) and M2-like tumor-associated macrophages (TAM-M2) contributes to tumor growth and metastasis. This research aims to investigate the regulatory mechanism of CCDC34 in the maintenance of this loop in lung squamous cell carcinoma (LUSC). Lentiviral vectors were used to knock down CCDC34, and the impact of CCDC34 knockdown on metastasis-like behaviors of LUSC cells was analyzed. LUSC cell-conditioned medium was used to analyze the influence of CCDC34 knockdown in LUSC on the M2 polarization of TAM and to verify the positive feedback loop of EMT and TAM-M2 polarization. CCDC34 was upregulated in LUSC and was related to poor patient prognosis. Knockdown of CCDC34 inhibited EMT in LUSC, decreased M2 polarization of TAM, impaired the positive feedback loop between EMT and TAM-M2 polarization, and suppressed metastasis of mouse LLC cells. TCF12 bound to the CCDC34 promoter to induce its transcription. Overexpression of CCDC34 overturned the blockade of EMT and TAM-M2 polarization by knockdown of TCF12 and promoted metastasis. Consequently, this study elucidates the essential roles of CCDC34 in the positive feedback loop between EMT and TAM-M2 in LUSC, thereby substantiating its potential as a prognostic marker.
Diabetic cataracts are a leading cause of blindness, with lens epithelial cells (LECs) exhibiting mitochondrial dysfunction and autophagy inhibition under high glucose (HG) conditions. Methyltransferase-like 14 (METTL14), an RNA methyltransferase, regulates N6-methyladenosine (m6A) RNA modification; however, its role in modulating mitochondrial function and autophagy in LECs under diabetic conditions remains poorly understood. This study aims to explore the effects of METTL14 on mitochondrial dysfunction and autophagy in LECs under HG conditions and to investigate the underlying mechanism involving m6A modification of ribosomal protein L3 (RPL3). Primary LECs exposed to HG showed reduced viability, increased reactive oxygen species (ROS), decreased adenosine triphosphate (ATP) levels, and loss of mitochondrial membrane potential (MMP), alongside suppressed autophagy. Knockdown of METTL14 worsened these deficits, while METTL14 overexpression alleviated them. Mechanistically, METTL14 increased m6A modification on RPL3 mRNA, enhancing RPL3 expression. Overexpressing RPL3 improved mitochondrial function, whereas knocking down RPL3 abolished the protective effects of METTL14 overexpression. In diabetic mouse models, adeno-associated virus (AAV)-mediated METTL14 overexpression improved lens transparency and reduced oxidative stress, benefits that were reversed by concurrent RPL3 knockdown. In conclusion, METTL14 mitigates HG-induced mitochondrial dysfunction and autophagy inhibition in LECs by promoting m6A-dependent upregulation of RPL3, identifying the METTL14/RPL3 axis as a promising target for diabetic cataract therapy.
Despite existing reports on the hepatoprotective effects of limonin (Lim), its specific impact on hepatic fibrosis and cellular senescence in metabolic dysfunction-associated steatohepatitis (MASH) remains unclear. The precise molecular mechanisms and direct targets underpinning its pharmacological activity are also poorly defined. This research aimed to investigate the therapeutic potential of Lim against MASH-related hepatic fibrosis and senescence, and to delineate the underlying molecular pathways. A murine MASH model was generated by feeding a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). To elucidate the mechanism of action of Lim, an integrated strategy was adopted, comprising AAV8-mediated gene manipulation, RNA sequencing (RNA-seq), and pharmacological interventions with agonists or inhibitors. The direct protein targets of Lim were identified using human proteome microarrays and validated through molecular docking, pull-down assays, and site-directed mutagenesis. Our findings indicate that Lim effectively alleviates hepatic fibrosis and senescence in MASH mice, while suppressing galectin-3 expression and mechanistic target of rapamycin complex 1 (mTORC1) activation. Notably, targeted knockdown of galectin-3 in the liver hindered aging-related changes in MASH mice, with mTORC1 functioning as a downstream effector. Further results revealed that mTORC1 acts as a key mediator of Lim's protective effects against hepatic fibrosis and senescence in MASH mice. Mechanistically, Lim binds to the Src homology 2 (SH2) domain of signal transducer and activator of transcription 3 (STAT3), inhibiting its activity and leading to reduced galectin-3 expression and mTORC1 activation. Moreover, the application of STAT3 inhibitor has been shown to alleviate hepatic fibrosis and senescence in MASH mice, further corroborating the suppression of galectin-3 and mTORC1 activity. In conclusion, our study provides compelling evidence for the efficacy of Lim in ameliorating hepatic senescence and fibrosis in MASH mice, elucidating the involvement of the STAT3/galectin-3/mTORC1 signaling in these processes.
The oncogenic transcription factor MYB is a genomic hallmark of adenoid cystic carcinoma (ACC), yet its downstream effectors and the underlying epitranscriptomic mechanisms remain incompletely understood. In this study, we combined bioinformatic analysis of clinical samples with mechanistic experiments in ACC cell lines and xenograft models, employing ChIP-qPCR, dual-luciferase reporter assays, acRIP-seq, meRIP-qPCR, RNA stability assays, and functional rescue experiments to investigate whether MYB drives ACC progression by orchestrating a functional crosstalk between key RNA modifications. We identified that MYB directly binds to the promoter of NAT10, the sole writer for N4-acetylcytidine (ac4C), and transcriptionally upregulates its expression. Subsequently, NAT10 installs ac4C modification on IGF2BP3 mRNA, enhancing its stability and increasing its expression, while IGF2BP3 in turn stabilizes NAT10 mRNA in an m6A-dependent manner, thereby forming a MYB-initiated, self-reinforcing circuit. Disruption of this circuit, either by knocking down NAT10/IGF2BP3 or by pharmacologically inhibiting NAT10 with Remodelin, attenuated the activation of the MAPK signaling pathway and suppressed ACC cell proliferation, migration, and invasion; importantly, Remodelin treatment significantly inhibited tumor growth in vivo. Collectively, our study unveils a novel oncogenic pathway in which MYB instigates a NAT10-IGF2BP3 RNA modification reciprocal regulatory circuit to promote ACC progression, highlighting the MYB-NAT10-IGF2BP3 axis as a promising therapeutic target for ACC.
CubeSats have emerged as an enabling technology for a new generation of space missions, offering relatively low cost and rapid development opportunities for scientific, educational, and technology demonstration. The reliable operation of a CubeSat depends critically on its electrical power system (EPS), which serves as the primary energy backbone for all onboard subsystems and payloads. Several studies have indicated that EPS as a subsystem is most susceptible to failure in the satellite missions, as it is under tight power, volume, and reliability constraints exposed to harsh and variable orbital conditions. In this context, this paper proposes the design, hardware implementation and experimental validation of an autonomous EPS architecture to enhance the operational lifetime of CubeSats. The proposed EPS autonomously manages energy to deal with solar irradiance variations in the low earth orbit (LEO). It combines maximum power point tracking (MPPT), battery management system (BMS), regulated power distribution and sensor based telemetry based on a microcontroller unit (MCU) controlled system. A real time decision making algorithm autonomously monitors the photovoltaic (PV) array voltage. The supervisory algorithm implements a three mode graduated control strategy, i.e. normal, moderate, and power-down. It is governed by two discrete PV voltage thresholds, enabling more precise and graduated load management compared to binary single threshold schemes reported in prior work. When nominal irradiance level is regained, the system returns autonomously to desired operational mode with no interference needed from the ground station. The modular design of the system allows to upgrade its components easily without the need to redevelop entire architecture. A detailed power budget analysis yields a total system load of 1,460mW, divided between telemetry (22mW), payload (1,400mW) and communication subsystems (38mW). The deployed EPS uses a Li-ion 3-cell battery pack (11.1V, each cell 1,800mAh) and PV panels of (12V, 2,100mW). Experimental tests validate the acquisition of data from various sensors and importantly accurate mode transition from normal to power down mode and vice-versa under fluctuating irradiance conditions. Furthermore, dynamic experiments involving controlled variation of PV voltage are also conducted to evaluate both degradation and recovery behavior of the system. The results demonstrate stable, repeatable, and threshold consistent mode transitions under varying input power scenarios. The results collectively demonstrate that autonomous mode transition and load management can be achieved using low cost commercial off the shelf components (COTS), making the proposed EPS a practical, reproducible, and scalable testbed for academic and small mission CubeSat platforms.
Intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), is closely associated with liver injury and ferroptosis. However, the molecular mechanisms underlying IH-induced liver damage remain largely unexplored. Here, we identify circ_38959 as a novel liver-protective circular RNA that mitigates IH-induced injury and ferroptosis. Circ_38959 overexpression in AML-12 hepatocytes significantly rescued cell viability, reduced apoptosis, and suppressed ferroptosis under IH conditions. Mechanistically, RNA immunoprecipitation uncovered that IGF2BP3 functions as a key interacting protein of circ_38959. Knocking down circ_38959 can down-regulate the protein expressions of IGF2BP3, c-Myc and c-Met. Functional studies revealed that IGF2BP3 deficiency abrogated the protective effects of circ_38959, confirming its essential role in liver protection and ferroptosis suppression. In an IH mouse model, AAV-mediated overexpression of circ_38959 effectively rescued liver function, and suppressed ferroptosis. Collectively, our study unveils a circ_38959-IGF2BP3 interaction that protects against IH-induced liver damage, highlighting circ_38959 as a potential therapeutic target for liver injury associated with OSA.
Diabetic foot ulcers (DFUs) are prevalent complication in diabetes. METTL14 serves as a key regulator of both autophagy and pyroptosis, both essential for the healing of DFUs. Simiao Yong'an Decoction (SYD) has demonstrated potential in promoting skin wound healing. This study investigates how METTL14 functions as a main regulator in DFU wound healing during SYD treatment and explores the underlying mechanisms. Both qPCR and western blot assays were performed to determine METTL14 and BECN1 expression. DFU rat models and fibroblasts stimulated with high glucose (HG) were used to evaluate the role of METTL14 in autophagy, pyroptosis, pro-angiogenic ability, and wound healing through both loss- and gain-of-function assays. The association between METTL14 and BECN1 was examined via MeRIP and RNA stability assays. Futhermore, the therapeutic effects of SYD on DFUs were assessed. Exposure to HG reduced METTL14 levels in fibroblasts, resulting in reduced cell viability and migration, lowered autophagy, and increased pyroptosis. Increasing METTL14 expression reversed these cellular impairments and enhanced angiogenesis driven by fibroblasts. Mechanistically, METTL14 stabilized BECN1 mRNA via m6A modification. In a rodent DFU model, overexpression of METTL14 accelerated wound healing, improved angiogenesis, and regulated autophagy and pyroptosis; these beneficial effects were partially reversed when BECN1 was knocked down. Furthermore, treatment with SYD increased METTL14 expression, promoted wound closure, angiogenesis, and autophagy, while reducing pyroptosis; these positive outcomes were significantly reduced when METTL14 was knocked down. METTL14-mediated m6A modification of BECN1 influences autophagy, pyroptosis, and angiogenesis to enhance wound healing in DFUs. METTL14 serves as a key regulator in SYD-mediated wound repair, offering a novel therapeutic strategy for treating DFUs.
Myasthenia Gravis (MG) is divided into ocular (OMG) and generalized (GMG) subtypes. While clinical diagnosis is well-established, understanding the underlying biochemical mechanisms and metabolic shifts during disease progression remains challenging; untargeted metabolomics offers a novel perspective to explore these systemic alterations. To characterize the serum metabolic landscape of MG patients and identify potential metabolic signatures associated with disease subtypes (OMG and GMG) via untargeted metabolomics. 91 participants (41 GMG, 22 OMG, 28 healthy controls [HC]) were enrolled. Fasting serum samples were analyzed by LC-MS/MS. Multivariate analyses (PCA, PLS-DA/OPLS-DA), differential metabolite screening (VIP > 1.0, p < 0.05), and KEGG pathway enrichment were performed. HC and MG groups showed distinct metabolic profiles. MG had 515 (175 up, 340 down) and 368 (146 up, 222 down) differential metabolites in positive/negative ion modes, respectively. Key perturbed pathways included glycerophospholipid, sphingolipid metabolism, and unsaturated fatty acid biosynthesis. Ten representative metabolites (e.g., ubiquinone, cortisol) differed significantly among groups; clustering analysis revealed distinct metabolite abundance trajectories across HC, OMG, and GMG. MG is associated with notable systemic metabolic dysregulation, particularly in lipid-related pathways. Rather than serving as immediate diagnostic tools, these integrative metabolic signatures provide a crucial biochemical framework for understanding disease pathogenesis and offer valuable clues for future hypothesis-driven research and prospective validation.
Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to various antibiotics, and identifying new antibiotics is urgently needed. Based on the structural modification of berberine (BBR), we discovered that 8-octyl berberine (OBBR) had stronger antibacterial activity, especially against MRSA, but its mechanism on MRSA has not been determined. This study revealed that, compared with vancomycin and BBR, OBBR exhibited superior in vitro and in vivo bactericidal activity against MRSA. More importantly, treatment with OBBR didn't develop resistance within 20 round of passages. Mechanistically, via membrane integrity assays and TEM, we observed that OBBR causes significant destruction of the MRSA cell wall and membrane. Transcriptomic and metabolomic analyses revealed that OBBR influenced the peptidoglycan biosynthesis pathway, and the expression of penicillin-binding protein 2a (PBP2a), a peptidoglycan synthesizing transpeptidase, was downregulated in MRSA after OBBR treatment. Further experiments (BOMD, CETSA, DARTs, SPR, GST pull-down and Co-IP) revealed that OBBR can result in an alteration of the spatial conformation of PBP2a and a strong binding interaction between them, and facilitate PBP2a degradation by interacting with ClpC of the AAA+ protease system. Overall, the potential mechanism of the anti-MRSA effect of OBBR is to promote PBP2a protein degradation via the AAA+ protease system rather than inhibiting the transpeptide activity of the PBP2a protein. Therefore, we propose a different bactericidal mechanism from that of β-lactam antibiotics and propose a novel drug candidate against MRSA in clinical settings.
High-fat diet (HFD), characterized by an increased proportion of palmitic acid (PA), can induce inflammatory responses in Sertoli cells, trigger apoptosis, and cause spermatogenic dysfunction. Endoplasmic reticulum stress (ERS) is intimately linked to inflammation, but whether ERS contributes to HFD-induced Sertoli cell inflammatory injury remains unclear. This study investigated how HFD and PA mediated Sertoli cell injury by upregulating inflammatory response at the in vivo and cellular levels. Obese mice and TM4 cell models were established using HFD and PA, respectively. The sperm quality of mice was systematically assessed. Key regulatory pathways were identified via transcriptome sequencing, and the mechanism underlying HFD-induced Sertoli cell injury was validated using Western blot and flow cytometry. The results showed that HFD could upregulate the expression of inflammatory cytokines in Sertoli cells by activating the NF-κB signaling pathway, ultimately leading to a reduction in Sertoli cell numbers. Through transcriptome sequencing, we found that PA could activate ERS in TM4 cells. After inhibiting the activity of ERS transmembrane protein inositol-requiring 1α (IRE1α), the apoptosis rate, inflammatory cytokine production, and the expression levels of NF-κB signaling pathway proteins in PA-stimulated TM4 cells were significantly decreased. Notably, inhibition of IRE1α protein activity significantly downregulated the expression of adaptor protein tumor necrosis factor 2 (TRAF2). Knocking down TRAF2 reduced the expression of both NF-κB signaling pathway proteins and inflammatory cytokines. Overall, this study provides a theoretical basis for preventing and treating HFD-induced male reproductive dysfunction by targeting the IRE1α/ TRAF2/NF-κB axis.
(±)-trans-3-methylfentanyl and (±)-cis-3-methylfentanyl are stereoisomeric analogues of 3-methylfentanyl. Although both exhibit high potency as µ-opioid receptor (MOR) agonists, their pharmacological profiles, such as analgesic potency, differ markedly. Current experimental data remain limited primarily to analgesia and MOR binding affinity. To comprehensively evaluate and compare the acute toxicity and the potency of abuse liability of (±)-trans-3-methylfentanyl and (±)-cis-3-methylfentanyl. Acute toxicity was assessed using the up-and-down procedure in mice. The potency of abuse liability was evaluated through four complementary paradigms: conditioned place preference (CPP), drug self-administration (SA), drug discrimination, and naloxone-precipitated withdrawal. In addition, dopamine D2 receptor (D2R) binding affinity was quantified in vitro using surface plasmon resonance (SPR), complementing in vivo behavioral findings. The median lethal dose (LD50) of (±)-trans-3-methylfentanyl and (±)-cis-3-methylfentanyl was identical and was 101 mg/kg (s.c.). The minimum doses to induce CPP were 30 µg/kg for (±)-trans-3-methylfentanyl and 3 µg/kg for (±)-cis-3-methylfentanyl, indicating a 10-fold higher potency of (±)-cis-3-methylfentanyl in inducing reward-associated learning. Conversely, in SA experiments, the peak dose to induce SA was 0.05 µg/kg/infusion for (±)-trans-3-methylfentanyl and 0.25 µg/kg/infusion for (±)-cis-3-methylfentanyl, demonstrating that the trans-isomer exhibits fivefold greater reinforcing potency. Drug discrimination experiment revealed that the discriminative stimulus potency of (±)-trans-3-methylfentany (ED50 = 0.29 µg/kg) was 1.4 times lower than that of (±)-cis-3-methylfentany (ED50 = 0.20 µg/kg). Repeated administration of (±)-trans-3-methylfentanyl and (±)-cis-3-methylfentanyl produced naloxone-precipitated withdrawal symptoms, confirming physical dependence liability. Notably, (±)-trans-3-methylfentanyl showed higher D2R binding affinity than (±)-cis-3-methylfentanyl in the SPR experiment. This study provides the first integrated assessment of acute toxicity and multifaceted abuse liability across key behavioral and molecular endpoints for these two stereoisomers. The divergent structure-activity relationships observed, particularly the inverse potency patterns in CPP versus SA and differential D2R engagement, highlight the critical influence of stereochemistry on neuropharmacological outcomes. These findings advance mechanistic understanding of fentanyl analogue action and inform future risk assessment and structure-based design of opioid therapeutics.
Sm3+-doped antimony-tungsten-phosphate glasses (designated SWNSm) with the composition (40 - x) Sb2O3-10WO3-50NaPO3-xSm2O3 (x = 0.15, 0.30, 0.45, 0.60, and 0.75 mol%) were prepared by the conventional melt-quenching-annealing technique. Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) analyses confirmed the amorphous nature and excellent thermal stability of the prepared glasses. Both experimental and theoretical elastic parameters, including Young's modulus (E) and Poisson's ratio (ν), were evaluated to verify that the incorporation of Sm3+ ions does not compromise the mechanical stiffness of the host glass. The measured density increased with increasing Sm2O3 content. Vibrational modes were identified using IR and FTIR spectroscopy. The optical bandgap values for all glass compositions were determined to lie in the range of 2.84-2.87 eV, confirming the insulating character of these glasses. Under 402 nm excitation, the down-conversion emission spectra exhibited characteristic transitions: 4G5/2 → 6H5/2 (560 nm), 4G5/2 → 6H7/2 (596 nm), 4G5/2 → 6H9/2 (643 nm), and 4G5/2 → 6H11/2 (707 nm). The observed up-conversion luminescence was interpreted in terms of excited-state absorption (ESA), energy transfer (ET), and cross-relaxation (CR) mechanisms. IR analysis revealed that the low phonon energy of the antimony-based glass host-evidenced by the dominant Sb-O-Sb stretching band at 602 cm-1-results in a reduced multiphonon relaxation rate, thereby facilitating efficient up-conversion processes. With increasing Sm3+ content, the measured fluorescence lifetime decreased from 1.815 to 1.710 ms, which is attributed to the increased concentration of OH- groups and the enhanced probability of ET among Sm3+ ions. The CIE chromaticity coordinates (x, y) fall within the orange-red region, indicating that these glasses are promising candidates for orange-red LED and solid-state laser applications.