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Positive allosteric modulators bind to secondary binding sites on the receptor and alter receptor conformation and activation, changing agonist potency and efficacy. PTC-174 is a novel NMDA receptor positive allosteric modulator that particularly enhances activity of receptors containing GluN2C or GluN2D subunits. We have investigated potentiation by PTC-174 of dopaminergic neuron NMDA responses, where receptors are likely to be GluN1/GluN2B/GluN2D triheteromeric receptors. Whole-cell and outside-out patch-clamp recordings from substantia nigra dopaminergic neurons in acute mid-brain slices from 6- to 8-day-old rats were used to investigate the effects of PTC-174 on NMDA responses and on NMDA receptor-mediated excitatory post-synaptic currents (EPSCs). A new 'hypercube' model with explicit receptor subunit-dependent binding steps for agonists and allosteric modulators was used to describe the effects of PTC-174. As expected, PTC-174 potentiated NMDA responses, with a >1.7-fold increase at 200-μM NMDA. The effect was independent of inhibition by the GluN2B-selective NAM ifenprodil when the two drugs were co-applied. In outside-out patches, PTC-174 increased channel open probability without altering the unitary current amplitude. PTC-174 prolonged the decay of NMDA receptor-mediated EPSCs and increased EPSC charge transfer. The results were described by a two-binding site subunit-specific 'hypercube' model that suggests PTC-174 reduces agonist microscopic affinity but enhances channel-gating efficacy. The main implication of the results in this paper is that PAMs like PTC-174 have the potential to enhance NMDA receptor signalling at substantia nigra dopaminergic neurons in vivo and so could enhance basal ganglia dopamine signalling.
We evaluated the effect of CYP2C19 genotype on SSRI response in 114,627 research participants. We graded metabolizer status (0 for ultrarapid metabolizers to 4 for poor metabolizers), and regressed drug response outcomes on these grades. Among participants taking escitalopram or citalopram, slower metabolizers experienced side effects significantly more often than faster metabolizers (OR = 1.04 per grade, 95%CI = [1.02-1.06] and OR = 1.05 per grade, 95%CI = [1.02-1.07]) and were more likely to discontinue treatment due to side effects (OR = 1.05, 95%CI = [1.03-1.08], e.g. 29.7% of poor vs. 21.6% of ultrarapid metabolizers, and OR = 1.07, 95%CI = [1.04-1.11], e.g. 25.7% vs. 20.2%). Slower metabolizers taking escitalopram were more likely to suffer from sleep problems and sexual problems. Slower metabolizers taking sertraline reported tremor more often than faster metabolizers. Overall, we find substantial differences in side effect risk with different CYP2C19 genotypes, supporting the notion that individuals seeking depression treatment may benefit from pharmacogenetic-guided treatment selection to minimize side effects and reduce discontinuations.
To examine the effectiveness of virtual reality-assisted neuromuscular training interventions on agility performance and injury prevention indicators in basketball athletes compared to conventional training approaches. A 12-week controlled laboratory experiment was conducted with 70 university-level basketball athletes (age 20.95 ± 1.5 years) randomly allocated to VR-assisted neuromuscular training (n = 35) or conventional training control groups (n = 35). Comprehensive assessments included agility tests (T-test, 5-10-5 shuttle), functional movement screening, biomechanical analysis, and neuromuscular function parameters measured at baseline, mid-intervention, and post-intervention. The VR training group demonstrated 7-10% greater pre-to-post improvements in agility performance compared with the control group across multiple agility measures (p < 0.001, Cohen's d = 0.89-1.34). Neuromuscular function parameters showed 15-30% greater pre-to-post improvements in the VR group relative to controls, including enhanced dynamic balance (pre-VR: 2.34 ± 0.41, post-VR: 1.67 ± 0.28; pre-control: 2.31 ± 0.38, post-control: 2.02 ± 0.35; between-group difference: - 0.35, 95% CI [- 0.52, - 0.18], effect size = 1.24, p < 0.001), improved joint position sense (23.4 vs. 11.8% improvement, 95% CI for difference [8.2%, 15.0%], p = 0.002), reduced dynamic knee valgus angles (18.7 vs. 8.2% reduction, 95% CI for difference [6.1%, 14.9%], p < 0.001), and increased reactive strength index (27.2 vs. 12.3% increase, 95% CI for difference [9.5%, 20.3%], p < 0.001). Movement quality scores and biomechanical injury risk markers consistently favored the VR intervention. Virtual reality-assisted neuromuscular training yields superior improvements in both agility performance and biomechanical injury risk markers compared to conventional training approaches in basketball athletes, supporting its integration into comprehensive athletic development programs.
Neuropathic pain (NeuP) is widely underdiagnosed, and treatment-related adverse events often drive nonadherence. We investigated the probable NeuP prevalence, symptoms recognition, and treatment preferences among the general population in Malaysia. We utilized a digital ID-Pain questionnaire across nine tertiary hospitals to screen for probable NeuP. We also designed a discrete choice experiment (DCE) to assess participants' ability to differentiate NeuP from nociceptive symptoms and to evaluate treatment preferences across five attributes (perceived pain reduction, time to effect, proven effectiveness, risk of common side effects, and cost) among the general population. The screening cohort included 13 592 adults (17.1% with diabetes). The overall prevalence of screen-positive for probable NeuP was 18.3% in the general population, increasing to 40.1% among people with diabetes. In the DCE cohort (n = 3999), 82.1% of participants demonstrated poor-to-moderate NeuP symptom recognition. Regarding treatment preferences, avoiding a high risk of common side effects was the primary driver of choice (coefficient -1.744, 95% CI -1.820, -1.669), followed by the desire for strong scientific evidence (coefficient 1.237, 95% CI 1.182, 1.291). Apart from clinical attributes, participants showed significant cost sensitivity (coefficient -5.565, 95% CI -6.909, -4.221). Despite a high prevalence of probable NeuP, poor symptom recognition creates a significant diagnostic challenge. Given that aversion to side effects is prioritized over other attributes, clinicians need to focus on tolerable anti-neuropathic agents and employ proactive side-effect management to optimize NeuP treatment adherence.
Although digital prosthodontic workflows have improved anatomic data acquisition for articulator mounting and jaw simulation, virtual articulator systems still commonly rely on average intercondylar distance values and standardized mounting procedures, limiting the simulation of patient-specific mandibular movement. The purpose of this in vitro study was to evaluate the feasibility of estimating sagittal condylar inclination (SCI) from facial scan-derived eccentric mandibular positional data in a temporomandibular joint (TMJ) simulation model and to investigate whether intercondylar distance influences measurement behavior. This study used a TMJ simulation model with intercondylar distance set at 5 levels (90, 100, 110, 120, and 130 mm) and SCI set at 4 levels (0, 15, 30, and 45 degrees). For each condition, facial scans at maximum intercuspation position (MIP), protrusive, right lateral, and left lateral positions were acquired as a single acquisition cycle, with 15 repeated cycles per condition. Eccentric scans were aligned to the MIP scan, and mandibular anterior transformation matrices were derived and mapped to the hinge axis to calculate SCI and the Bennett angle. Agreement between measured and actual SCI was evaluated using a mixed-effects Bland-Altman approach. Supportive analyses included linear regression, signed and absolute error, root mean square error (RMSE), mixed-effects modeling of SCI absolute error, and intraclass correlation coefficient (ICC) for repeatability. The mixed-effects Bland-Altman analysis showed a negative overall bias (-1.07 degrees; 95% confidence interval (CI), -1.78 to -0.36), with broad individual-measurement variability. Supportive regression analyses showed slopes not significantly different from 1 and intercept confidence intervals including 0. Pooled mean ±standard deviation absolute error was 4.56 ±4.34 degrees, and RMSE was 6.29 degrees. For SCI absolute error, actual SCI was significant, whereas the side, intercondylar distance, and intercondylar distance×actual SCI interaction were not. Overall ICC was 0.886 (95% CI, 0.819 to 0.919). Descriptively, the Bennett angle showed significant negative correlations with intercondylar distance and positive correlations with actual SCI in most, but not all, distance conditions. Based on the findings of this in vitro TMJ simulation study, facial scan- and eccentric position-based SCI estimation showed generally stable measurement performance across the evaluated conditions, with no statistically detectable systematic effect of intercondylar distance on SCI error under the evaluated simulator-based conditions.
Bone remodeling requires precise coordination between osteoblast-mediated bone formation and osteoclast-driven resorption. However, directly targetable and therapeutically actionable mediators that can coordinately modulate both processes during regeneration remain relatively limited. Here, we identify immunoglobulin superfamily member 10 (IGSF10) as a dual-function modulator of bone remodeling. Igsf10-deficient mice exhibit reduced bone mass, elevated osteoclast activity, and impaired osteogenesis. Recombinant IGSF10 protein restores osteogenic capacity and suppresses osteoclastogenesis in knockout cells, while exerting pro-osteogenic and anti-resorptive effects in wild-type mesenchymal and monocyte-derived cultures. Mechanistically, IGSF10 activates a noncanonical EGFR-STAT1 signaling pathway, distinct from BMP2-Smad signaling. Co-immunoprecipitation and molecular docking confirm IGSF10-EGFR interaction, and blockade of EGFR abrogates IGSF10-induced osteogenesis and its inhibitory effects on osteoclastogenesis. In vivo, IGSF10 promotes bone regeneration in both calvarial and periodontal defect models and exhibits synergy with subtherapeutic BMP2. These findings position IGSF10 as a previously unrecognized dual-acting regulator that coordinates bone formation and resorption in a context-dependent manner, with potential therapeutic value for craniofacial and skeletal regeneration.
Platinum resistance remains a major therapeutic challenge in ovarian cancer (OC) and is one of the main causes leading to disease relapse and mortality. Although PARP inhibitors have improved outcomes for a subset of patients, most women continue to rely on platinum-taxol based chemotherapy and ultimately develop recurrent, treatment-resistant disease with limited further therapy options. Therefore, there is a critical need to identify actionable, patient-specific vulnerabilities that would help as an alternative for chemoresistant patients. To identify such therapeutic opportunities, we established 35 patient-derived models from 22 OC patients, representing seven OC subtypes and preserving key molecular features of individual patients. High-throughput drug profiling across a library of 528 oncology-focused compounds generated over 29,000 drug response measurements, revealing inter-patient heterogeneity and sensitivity patterns. Among these, a subset of models exhibited a pronounced dependency on the anti-apoptotic protein Bcl-xL with minimal effects observed on patient-derived fibroblasts and healthy bone marrow, suggesting a therapeutic window. Proteomics-based comparison of Bcl-xL-sensitive and -resistant subclones identified activation of NOTCH signaling as a determinant to reduced response to Bcl-xL inhibition. Blocking of NOTCH signaling with gamma-secretase inhibitors restored sensitivity to Bcl-xL targeting and resensitized resistant cells to Carboplatin, resulting in sustained cytotoxicity in long-term washout assays and ex vivo cultures. Similar effects were observed with both Bcl-xL protein degrader and small molecule inhibitor, supporting robust targeting of Bcl-xL through different modalities. Together, these findings define a NOTCH-modulated Bcl-xL survival axis as a therapeutic vulnerability in platinum resistant OC. More broadly, this study demonstrates how translational drug profiling of physiologically relevant disease models can generate insights with clinical potential and provide precision oncology framework for identifying rational combination strategies to overcome chemoresistance.
Despite the rapid global expansion of legal bans on child corporal punishment, little is known about whether these policies are associated with adolescents' experiences of peer violence. Drawing on cross-national data from the Programme for International Student Assessment (PISA) 2022, this study included 22,721 students from 31 OECD countries and regions to examine the association between national corporal punishment bans and bullying victimization among adolescents. Multilevel linear modeling was employed to account for the hierarchical structure of the data. The results indicate that more comprehensive and longer standing national bans on corporal punishment are associated with lower levels of bullying victimization among adolescents. Mediation analyses further reveal that peer cooperation partially explains this association, suggesting that social competencies may represent an important pathway linking institutional contexts to adolescents' peer experiences. In addition, moderation analyses indicate that the association between corporal punishment bans and bullying victimization is more pronounced among boys than among girls. These findings highlight the potential spillover effects of child protection legislation beyond the family context and underscore the importance of social competencies and gender sensitive perspectives in understanding adolescents' exposure to peer violence. Overall, the study contributes new cross national evidence on the broader societal implications of corporal punishment bans and provides insights for policies aimed at preventing violence against children and adolescents.
Kidney diseases, represented by chronic kidney disease (CKD) and acute kidney injury (AKI), pose significant global public health challenges due to their complex pathogenesis and limited therapeutic options. In recent years, epigenetic regulation-including DNA methylation, histone modifications, and non-coding RNAs-has been shown to play a crucial role in the progression of kidney diseases, offering new directions for therapeutic strategies. Natural herbal compounds have emerged as a research focus for modulating epigenetic mechanisms owing to their multi-target effects, low toxicity, and broad bioactivity. This review outlines the regulatory functions of epigenetic mechanisms across various kidney diseases and illustrates how natural herbal compounds can mitigate renal injury via multi-target epigenetic modulation. These compounds have been shown to reverse renal fibrosis, attenuate inflammatory responses, suppress oxidative stress, and protect podocytes and renal tubular epithelial cells by targeting DNA methyltransferases, histone-modifying enzymes, and non-coding RNAs, including microRNAs and long non-coding RNAs. However, challenges such as limited bioavailability and insufficiently elucidated in vivo mechanisms impede clinical translation. Future research should prioritize structural optimization, advanced delivery systems, and investigations into gut microbiome interactions to enhance therapeutic applicability. Overall, this review highlights the promise of epigenetics-based therapeutic strategies using herbal active ingredients for kidney disease intervention, though further validation and optimization are needed for clinical application.
Distinguishing objects from the background, a process known as Object Individuation (OI), is fundamental for us to interact with the environment and relies critically on location information across sensory modalities. Nonetheless, it remains unclear and contested in the literature whether the enumeration of tactile and visual events relies on the OI process (especially given spatial constraints), or if the representation of numerosity is governed by a modality-independent mechanism common to both visual and tactile systems. In this study, we used a cross-modal enumeration and a working memory dual-task paradigm to investigate whether OI processes in tactile and visual modalities draw upon a shared cognitive resource. We implemented two experiments. In Experiment 1, we combined a tactile working memory (WM) task with visual enumeration, and in Experiment 2, we used a visual WM task with tactile enumeration. Both experiments revealed that the task-irrelevant WM load significantly modulated subitizing performance (enumeration of small quantities) in the target modality. Under high WM load, participants showed increased error rates and reduced subitizing capacity compared to low load. This modulation is selective to the subitizing range and cannot be attributed to general dual-task costs, ruling out general dual-tasking effects. The data shows that visual and tactile working memory and enumeration ("subitizing") share a common OI process that operates on location, independent of the sensory modality. This finding is consistent with existent neuroimaging evidence that highlights the modality-shared role of frontoparietal brain regions (e.g., IPS, LPFC) in enumeration and working memory.
Elevated remnant cholesterol (RC) is implicated in the pathogenesis of atherosclerosis. To assess the prognostic role of RC in atherosclerotic cardiovascular disease. We systematically searched PubMed, Embase, the Cochrane Library, and Web of Science from inception to January 18, 2026, for eligible studies. The primary outcome was a composite of major adverse cardiovascular events (MACE). Pooled hazard ratios (HRs) with 95% CIs were calculated using a random-effects model. Twenty-one studies involving 114,592 participants were included. Higher RC levels were significantly associated with an increased risk of MACE (HR: 1.44, P < .001), all-cause mortality (HR: 1.40; P < .001), myocardial infarction (MI) (HR: 1.35; P < .001), stroke (HR: 1.21; P = .004), cardiac death (HR: 1.41; P < .001), and unplanned repeat revascularization (HR: 1.56; P < .001). Furthermore, each 1-SD increment in RC level was associated with an elevated risk of MACE (HR: 1.22; P < .001), all-cause mortality (HR: 1.16; P = .010), MI (HR: 1.11; P < .001), and unplanned repeat revascularization (HR: 1.31; P = .007). The association between RC levels and MACE risk was potentially modified by geographic region, body mass index, current smoking status, adjustment for traditional lipid parameters, and study quality. Elevated RC is associated with a worse prognosis in patients with established coronary artery disease. This association persisted after adjustment for traditional cardiovascular risk factors in the included studies, although residual confounding cannot be excluded. These findings suggest that RC assessment may have potential value within secondary prevention strategies for coronary artery disease.
This systematic review with functional meta-synthesis and exploratory meta-analysis evaluated the clinical utility of molecular testing in ameloblastoma, focusing on diagnostic, genotype-phenotype, prognostic, liquid-biopsy, and precision-therapy implications. PubMed/MEDLINE, Scopus, and Embase were searched from inception to April 2026. Eligible studies were full original articles evaluating direct molecular or molecularly interpretable testing in human ameloblastoma. Data were synthesized using functional meta-synthesis. Exploratory random-effects meta-analyses were performed when sufficient study-level data were available. Twenty-nine studies met the inclusion criteria. Molecular testing was most consistently informative for defining the molecular landscape and supporting diagnosis. BRAF V600E was the dominant alteration across the evidence base, but additional alterations in SMO, FGFR2, RAS-family genes, CTNNB1, PIK3CA, EGFR, and ROS1 were reported, particularly in selected or BRAF-wild-type tumors. Exploratory meta-analysis of 19 studies showed a pooled BRAF V600E prevalence of 69.1% (95% CI: 62.1%-75.3%; I2 = 80.3%). Four studies provided complete site-specific data, showing strong enrichment of BRAF V600E in mandibular versus maxillary tumors (OR = 20.13; 95% CI: 7.65-52.95; I2 = 0.0%). BRAF VE1 immunohistochemistry showed high exploratory pooled sensitivity (96.6%; 95% CI: 84.1%-99.4%) and specificity (89.8%; 95% CI: 71.5%-96.8%) when compared with molecular reference methods. Prognostic evidence was inconsistent: BRAF V600E was not a reliable stand-alone recurrence marker, although VEGF mRNA and broader molecular profiles may have prognostic relevance. Plasma cfDNA testing did not reliably detect tissue-positive BRAF V600E. Targeted therapy evidence suggested radiologic response and organ-preservation potential in selected BRAF V600E-mutated tumors, but remained limited to non-randomized series. Molecular testing provides clinically relevant diagnostic and genotype-phenotype information in ameloblastoma and may guide targeted therapy in selected cases. Prognostic and liquid-biopsy applications remain insufficiently validated.
This study presents the fabrication of a novel, sustainable, and cost-effective hybrid composite (SAC-PANI) derived from sewage sludge calcined at 600 °C, activated carbon, and polyaniline through in situ oxidative polymerization. Comprehensive Characterization using FTIR, XRD, SEM, BET, and TGA confirmed the successful formation of the composite and its enhanced physicochemical properties. BET analysis revealed a substantial increase in surface area (90 m²/g) compared to raw calcined sludge (58 m²/g), indicating improved porosity. Process optimization was performed using Response Surface Methodology (RSM) based on a Central Composite Design (CCD). The developed quadratic model (R² = 0.984) adequately described the system and revealed significant interactions among pH, adsorbent dosage, and initial metal concentration, with optimum removal achieved at pH 6.0. Adsorption equilibrium data were best described by the Langmuir isotherm (R² = 0.995 and 0.992 for Pb(II) and Cd(II), respectively), yielding maximum adsorption capacities of 128.5 ± 2.3 mg/g for Pb(II) and 115.7 ± 2.1 mg/g for Cd(II). Kinetic studies were well fitted by the pseudo-second-order model (R² = 0.998 for Pb(II) and 0.997 for Cd(II)), with rate constants of k₂ = 0.035 ± 0.001 g/mg·min for Pb(II) and k₂ = 0.029 ± 0.001 g/mg·min for Cd(II), indicating that chemisorption is the dominant adsorption mechanism owing to interactions between the metal ions and the nitrogen-containing functional groups of PANI. Thermodynamic analysis demonstrated that the adsorption process is spontaneous (ΔG° = -19.8 kJ/mol for Pb(II) and - 17.6 kJ/mol for Cd(II) at 298 K), endothermic (ΔH° = +33.5 kJ/mol for Pb(II) and + 25.3 kJ/mol for Cd(II)), and characterized by increased entropy (ΔS° = +132 J/mol·K for Pb(II) and + 98 J/mol·K for Cd(II)), indicating chemisorption-driven metal uptake. The composite also exhibited good stability, retaining more than 82% of its removal efficiency after five adsorption-desorption cycles for both Pb(II) and Cd(II).). Environmental safety assessment via the TCLP leaching test demonstrated that the spent adsorbent is non-hazardous, with Pb and Cd leachate concentrations (0.58 and 0.18 mg/L, respectively) well below EPA regulatory limits (5.0 mg/L for Pb and 1.0 mg/L for Cd). Importantly, the SAC-PANI composite was successfully tested on real electroplating wastewater, achieving Pb(II) and Cd(II) removal efficiencies of 75.0 ± 1.5% and 72.6 ± 1.4%, respectively, in the presence of competing ions and complex matrix effects. Overall, SAC-PANI demonstrates considerable potential as an efficient, sustainable, and low-cost adsorbent for the removal of heavy metals from wastewater.
Minimally invasive surgery (MIS) for spontaneous supratentorial intracerebral hemorrhage (sICH) includes endoscopic evacuation and catheter-based evacuation (aspiration or drainage ± thrombolysis), but comparative performance remains uncertain. We performed a systematic review and meta-analysis comparing MIS approaches. PubMed, Embase, and CENTRAL were searched (December 2025) for studies in adults undergoing endoscopic or catheter-based MIS for supratentorial sICH. Random-effects meta-analysis was conducted. Prespecified subgroup analyses stratified catheter-based techniques by thrombolysis use. Risk of bias and certainty of evidence was assessed. Twenty-nine studies (8221 patients; 5041 endoscopic; 3180 catheter-based) were included. Endoscopic evacuation was associated with lower mortality (RR 0.64; 95% CI: 0.47-0.87; P < 0.01; I2 = 44.8%), rebleeding (RR 0.58; 95% CI: 0.39-0.87; P < 0.01; I2 = 22.2%), postoperative hematoma volume (MD -5.6 mL; 95% CI: -10.30-0.90; P < 0.05; I2 = 96.9%), and higher day-one evacuation rate (MD 24.5%; 95% CI: 14.60-34.40; P < 0.001; I2 = 99.7%). Overall complications (RR 0.98; 95% CI: 0.78-1.25; P = 0.90; I2 = 48.5%) and infection (RR 1.03; 95% CI: 0.64-1.66; P = 0.05; I2 = 43.6%) were similar. Catheter-based approaches had lower intraoperative blood loss (MD 69.0 mL; 95% CI: 27.7-110.4; P < 0.001; I2 = 96.9%). Subgroup analyses suggested that mortality and evacuation rate differences favored catheter-based cohorts receiving thrombolysis. Functional outcomes diverged: GCS/GOS favored endoscopy (SMD 0.27) while mRS marginally favored catheter-based approaches (MD 0.28), a between-group difference below the threshold generally considered clinically meaningful. Endoscopic evacuation was associated with lower mortality, rebleeding, and residual hematoma burden, while catheter-based approaches retained perioperative efficiency advantages. Functional findings were mixed and of uncertain clinical significance. Given predominantly non-randomized evidence and heterogeneity, these findings should be interpreted as strategy-specific associations.
One-electron oxidants that include type I photosensitizers, biologically relevant carbonate anion radical generators, and high intensity UVC nanosecond lasers are able to ionize in aqueous solution purine and pyrimidine nucleobases. The survey is aimed at critically reviewing the available information on the fate of initially generated base radical cations that essentially involve deprotonation and nucleophilic addition reactions. Accumulated evidence leads to the conclusion that one-electron oxidation reactions of nucleobases partly mimic the oxidizing features of hydroxyl radical, the main biologically relevant oxidant, in terms of formed degradation products. In contrast to the relatively nonspecific attack of hydroxyl radicals, guanine sites are the main targets of one-electron oxidation. This may be rationalized by efficient redistribution of base radical cations through charge transfer along double-stranded DNA with preferential final product formation at guanines, as illustrated by the overwhelming formation of 8-oxo-7,8-dihydroguanine. Interestingly, a similar observation was made for cellular DNA; thus, providing strong support for the occurrence of hole migration in model DNA substrates as well as in cells. The specific distribution of DNA degradation products displayed by one-electron oxidants was used to provide further support for the modest role of direct effects of ionizing radiation in the oxidative degradation of cellular DNA.
Irregular spatial sampling, acquisition gaps, and operational constraints compromise the resolution and fidelity of seismic imaging, often causing aliasing, amplitude distortions, and migration artifacts that hinder structural interpretation and reservoir characterization. This research evaluates five-dimensional (5D) regularization and interpolation for reconstructing incomplete seismic datasets. The study applies 3D seismic data from the Bazuzi Field, Sirte Basin, North Libya-a region characterized by sparse shot-receiver spacing and irregular offset-azimuth coverage. By integrating 5D interpolation into the pre-stack domain (inline, crossline, offset, azimuth, and time), a continuous, uniformly sampled wavefield is reconstructed, providing optimized input for imaging. The workflow incorporates data conditioning, Fourier-based interpolation, Radon transforms, and least-squares optimization for trace reconstruction. Comparative assessment between the nominal grid (250 × 250 m) and an upsampled interpolated grid (125 × 125 m) demonstrates significant improvements. Nominal fold coverage increases from 120 to 480 traces per 25 × 25 m bin, offset-azimuth sampling is enhanced, and acquisition footprints are suppressed. 5D interpolation restores missing traces while preserving amplitude fidelity, enabling more reliable AVO/AVA analysis. Upsampled interpolation improves structural continuity, reduces migration smiles and edge effects, and increases signal-to-noise ratio across in-line and cross-line sections. Quality control on time slices, offset classes, and CDP gathers confirm improved geological plausibility and kinematic consistency. These results underscore the ability of 5D techniques to mitigate acquisition limitations and enhance seismic imaging. With growing computational power, 5D regularization is poised to become increasingly central to high-resolution subsurface interpretation and hydrocarbon exploration.
Radiation-induced intestinal injury (RIII) severely compromises the quality of life in patients undergoing abdominal/pelvic radiotherapy and may necessitate treatment discontinuation. To date, there is no approved agent for the prevention or treatment of RIII. This study aims to clarify the protective effects of mannose on RIII and elucidate its mechanisms of action, in order to identify new safe and effective therapeutic agents and potential therapeutic targets for the prevention and treatment of RIII. Here, we report that intraperitoneal administration of mannose, a natural bioactive monosaccharide, at 24, 12, and 2 h prior to lethal irradiation increased the survival rate of mice from 0% to 50%. Specifically, mannose pretreatment significantly blocked crypt cell apoptosis, preserved epithelial barrier integrity, attenuated intestinal inflammation, and enhanced crypt regeneration. Additionally, mannose treatment enhanced the survival of intestinal stem cells both in vitro and in vivo following radiation exposure. We further confirmed that mannose maintains mitochondrial homeostasis and alleviates cellular oxidative stress. Moreover, mannose facilitated the repair of DNA double-strand breaks, thereby inhibiting aberrant mitosis after radiation exposure. Additionally, preliminary evidence indicates that mannose does not affect the radiosensitivity of colorectal tumor cells or azoxymethane/dextran sodium sulfate-induced colorectal tumors in mice.Conclusion and Innovation:Given its low toxicity and wide availability, our findings suggest that mannose represents a promising protective strategy for RIII. Antioxid. Redox Signal. 00, 000-000.
The purpose of this research is to examine the effects of organic pain beliefs (OPB) and psychological pain beliefs (PPB) on pain intensity, disability, kinesiophobia, catastrophizing, and pain knowledge in chronic shoulder pain. Cross-sectional observational study. In this cross-sectional study, 109 patients (66 females, 43 males; mean age 49.8 ± 10.4 years) with chronic rotator cuff-related shoulder pain were recruited using a convenience sampling method and completed the Pain Beliefs Questionnaire (PBQ), the Numeric Pain Rating Scale (NPRS), the Shoulder Pain and Disability Index (SPADI), the Tampa Scale for Kinesiophobia (TSK), the Pain Catastrophizing Scale (PCS), and the Revised Pain Neurophysiology Questionnaire (Revised-NPQ). Pearson correlation and multiple linear regression analyses were used to assess the relationships of OPB and PPB with the outcome measures. OPB were significantly positively correlated with activity-related pain (r = 0.30, p = .001), disability (SPADI total; r = 0.21, p = .025), kinesiophobia (TSK; r = 0.42, p < .001), and catastrophizing (PCS; r = 0.40, p < .001), and were negatively correlated with Revised-NPQ (r=-0.34, p = .001). In multiple regression models, OPB significantly predicted greater disability (β=0.25, p = .013), kinesiophobia (β=0.45, p < .001), and catastrophizing (β=0.44, p < .001), explaining 4.8%-17.4% of variance in these outcomes (adjusted R²=0.048-0.174). In chronic shoulder pain, OPB show weak to moderate associations with adverse clinical outcomes and a negative association with pain knowledge, whereas PPB are not significantly related to outcomes. These findings support the potential value of targeting maladaptive beliefs and improving pain knowledge within rehabilitation. Evaluating OPB and PPB in relation to pain-related parameters, kinesiophobia, and catastrophizing may help identify at-risk patients and support individualized rehabilitation and targeted education in chronic shoulder pain.
Xylazine and medetomidine are veterinary sedatives increasingly detected as adulterants in the U.S. illicit drug supply. In response, several states have scheduled xylazine; none have scheduled medetomidine during the study period. Whether xylazine scheduling was associated with subsequent changes in xylazine and medetomidine detections remains unclear. We conducted a state-level, semiannual, serial cross-sectional study using National Forensic Laboratory Information System (NFLIS) data on drug samples from 1999 to 2025. The primary outcomes were xylazine and medetomidine reports per 100,000 NFLIS drug reports. We used staggered difference-in-differences event-study models to estimate changes in report rates after xylazine scheduling. Sensitivity analyses excluded Florida and expanded the treatment definition to include states that criminalized xylazine without formal scheduling. Falsification analyses examined steroid and antidepressant reports as negative-control outcomes. NFLIS recorded 101,987 xylazine reports and 12,085 medetomidine reports. Xylazine scheduling was not associated with a significant change in xylazine report rates (ATT, 2872.3 per 100,000; 95% CI, -2024.6 to 7769.2; p=.250). In contrast, xylazine scheduling was associated with a significant increase in medetomidine report rates (ATT, 1536.5 per 100,000; 95% CI, 211.1 to 2861.9; p=.023). Sensitivity analyses produced similar findings. Negative-control outcomes showed no significant changes. State xylazine scheduling was associated with increases in medetomidine reports but no significant change in xylazine reports. These findings suggest that scheduling may be followed by changes in adulterant composition rather than reductions in overall α2-adrenergic agonist involvement. Our study highlights the importance of monitoring the unintended effects of xylazine scheduling and supporting continued investment in public health surveillance, drug checking, and harm reduction services.
Tauopathies are neurodegenerative disorders characterized by accumulating misfolded, insoluble tau protein aggregates in neurons or glial cells. In this study, we screened the Spectrum Collection and other compound libraries for inhibitors of tau self-interaction using a structural complementation reporter system (NanoLuciferase Binary Technology). Resulting candidates were tested in dose-response assays and evaluated for cell toxicity and microtubule destabilization. Further, a seed-induced tau interaction biosensor assay and a cell-free tau Real-Time Quaking-Induced Conversion assay have been established to study their effects on the kinetics of tau interaction and aggregation, respectively. The substances ritanserin, 3-methoxycatechol, gambogic amide, azaoxafluorenes VT11, and NS 185 and thieno[2,3-d][1.3]oxazine B6/55 showed a concentration-dependent tau self-interaction inhibition without relevant cell toxicity or microtubule destabilization. Ritanserin, VT11, NS 185 and B6/55 blocked tau interaction in the seed-induced tau interaction biosensor assay. Finally, the cell-free tau RT-QuIC assay displayed highest inhibitory potential for VT11. Thus, the azaoxafluorene VT11 seems to be a promising candidate for further investigations as tau interaction inhibitor to address a pivotal pathological process in Alzheimer's disease and other tauopathies.