Search Results (796)

The clinical renaissance of psychedelic medicine has highlighted the therapeutic potential of rapid-acting neuroplastogens, or “psychoplastogens,” for psychiatric disorders. However, the widespread application of classical psychedelics—such as psilocybin and LSD—and the atypical dissociative ibogaine is severely limited by their hallucinogenic properties and, particularly in the case of ibogaine, life-threatening cardiotoxicity. Addressing these limitations, Tabernanthalog (TBG) has emerged as a frontrunner in the field. This non-hallucinogenic analog of ibogaine was rationally designed to eliminate interactions with the human ether-à-go-go-related gene (hERG, KCNH2) potassium channel, thereby mitigating cardiotoxic risks. While initially characterized for its anti-addictive and antidepressant-like properties, recent data from 2024–2025 have significantly expanded its therapeutic horizon. TBG demonstrates robust efficacy in preclinical models of neuropathic and visceral pain, as well as in the rescue of cognitive deficits associated with cancer-related cognitive impairment (CRCI). TBG has shown efficacy in reversing cognitive impairments induced directly by the presence of a tumor in preclinical models, rather than by chemotherapy-specific neurotoxicity. Crucially, emerging evidence suggests that TBG’s mechanism extends beyond simple 5-HT2A receptor agonism. New findings point to a multi-target profile involving the inhibition of nicotinic acetylcholine receptors (nAChRs), positive modulation of NMDA receptors, and functional crosstalk with mGlu2 receptors. Furthermore, TBG appears to induce structural neuroplasticity without the widespread induction of immediate early genes (IEGs) seen with classical hallucinogens, suggesting a decoupling of therapeutic rewiring from the subjective psychedelic experience. This review synthesizes current preclinical evidence to discuss TBG as a promising chemical scaffold for next-generation neurotherapeutics targeting the intersection of psychiatry and neurology. Full article

Background and Objectives: Cross-country skiing requires high levels of upper-body strength and efficient respiratory function to sustain performance during sport-specific movements. This study aimed to examine the effects of an eight-week ski ergometer-based training program on upper-extremity isokinetic muscle strength and pulmonary function in competitive cross-country skiers. Materials and Methods: A total of 20 cross-country skiers voluntarily participated in the study (experimental group: n = 10, control group: n = 10). The research was conducted using a quasi-experimental controlled design. During the eight-week training period, the experimental group performed ski ergometer training three times per week at an intensity of 80–90% of maximal heart rate, with a target distance of 2.5 km per session, in addition to their regular training program. Measurements were obtained before and after the intervention. Results: Following the ski ergometer training period, significant increases were observed in FVC (F = 18.565, p < 0.001, ηp² = 0.508) and FEV₁ (F = 8.789, p = 0.008, ηp² = 0.328), which were associated with enhanced respiratory muscle endurance and ventilatory capacity. Regarding the isokinetic strength parameters, the DPPE60 variable showed significant main effects of time (F = 33.770, p < 0.001, ηp² = 0.652) and time × group interaction (F = 18.590, p < 0.001, ηp² = 0.508), indicating higher upper-extremity strength values across the measurement period. Additionally, strong positive correlations were found between dominant and nondominant limbs (r = 0.79–0.92; p < 0.05), indicating balanced bilateral strength development and high neuromuscular coordination. Conclusions: Ski ergometer-based training was associated with improvements in upper-extremity peak power (DPPE60) and ventilatory capacity (FVC) beyond general training-related adaptations. These findings suggest that SkiErg training may be a useful complementary method for enhancing selected performance-related physiological parameters in cross-country skiers. Full article

Invasive fungal diseases (IFDs) represent an escalating global health threat, compounded by the rapid emergence of antifungal resistance (AFR). This review synthesizes the contemporary landscape of AFR from clinical and microbiological perspectives, providing actionable insights for clinical practitioners. We examine the epidemiology of critical pathogens, including Candidozyma auris, clonal Candida parapsilosis, azole-resistant Aspergillus fumigatus, and dissect the underlying molecular mechanisms, from genetic mutations in ERG11 and cyp51A to novel emerging epigenetic and adaptive strategies. We critically appraise the diagnostic gap between phenotypic testing and clinical urgency, highlighting the role of rapid molecular assays and next-generation sequencing. Finally, we evaluate evidence-based therapeutic strategies, including the integration of novel agents such as rezafungin, ibrexafungerp, olorofim, and fosmanogepix), while emphasizing the imperative of antifungal stewardship, infection prevention and control in mitigating resistance, and “One-Health” interventions. Full article

miRNA 183 is part of the miRNA-183/96/182 cluster, which is known to play a decisive role in fine-tuning the activity of gene expression in sensory systems, particularly in the retina. Although miR-183 is essential for retinal gene expression in mammals, the contributions of miR-183 to mRNA expression and photoreceptor development and function in other classes of animals have not been fully elucidated. Danio rerio have a diverse photoreceptor system, with cone photoreceptors sensitive to red, green, blue and ultraviolet (UV) light. We generated knockout zebrafish by deleting the whole seed sequence of miR-183. RNAscope results show no expression of mature miR-183 and decreased expression of miR-182 in both dorsal and ventral KO retinas. The number of UV and blue photoreceptors decreased, and the photoreceptors showed shortening or loss of their outer segments. In the absence of miR-183, the transcription levels of phototransduction genes were altered differentially at 3 and 12 months of age. Finally, photoreceptor-only electroretinogram (PIII) signals showed attenuated amplitudes of red and green-sensitive photoreceptor subtypes while the b-wave amplitudes reflecting second order retinal neuron activity, were decreased in response to the UV-, blue-, and red-stimulating wavelengths. These results reveal a novel microRNA regulatory network in teleost fish and indicate that miR-183 plays a facilitative role in retinal development and function, especially for short-wavelength-sensitive photoreceptor subtypes. Full article

In vitro studies were conducted in a series to investigate if the ruminal microbes are capable of degrading chlorpyrifos. This in vitro study presents the results from three experiments: Exp. I was conducted without feed, while Exp II and III were conducted with feed, either with or without methanol for dissolving chlorpyrifos, respectively. A basal diet comprising finger millet straw and concentrate was prepared. Incubation medium with feed but without chlorpyrifos served as the control. A total of six replicates each of control and chlorpyrifos spiked were used for the incubation. The pesticide concentration in the incubation medium before and after 24 h of incubation was analyzed using GC-MS/MS. The genomic DNA was isolated from the incubation fluid of the individual samples, and the shotgun metagenomic sequencing was performed. The clean reads were taxonomically classified using the Kraken2 database, and microbial classification at different taxonomic ranks was separated using Pavian v1.0. The microbial genes in the metagenome data were predicted and assigned functional roles using the MetaErg v1.2.3 pipeline. The assigned KEGG Orthology (KO), EC numbers (Enzyme Commission number), Gene Ontology (GO), and corresponding NCBI taxonomy information relevant to chlorpyrifos metabolism/degradation were retrieved. Results from the study revealed that the chlorpyrifos concentration was decreased from 5.78 to 1.64 ppm over 24 h of in vitro incubation with feed. Similar alpha and beta diversity indices between control and chlorpyrifos treatments revealed that the richness and the evenness of the microbial population were not affected by the presence of chlorpyrifos in the rumen fluid. There was no difference in the microbiota affiliated to the major phyla such as Bacteroidota, Fibrobacterota, Bacillota, and Pseudomonadota. The EC 3.1.8.1, EC 3.1.3.1, EC 1.14.13.-, and EC 1.1.1.- reported for chlorpyrifos degradation were not detected in the metagenome, and only EC 3.1.1.1 was identified, which demonstrated that degradation of chlorpyrifos was carried out by the affiliated enzyme carboxylesterase. The presence of GO:0004035, GO:0004364, GO:0019637, GO:0016791, and GO:0042178 in the metagenome strengthens that the chlorpyrifos degradation in the present study was primarily assigned to the rumen microbiota. This in vitro study provided insights into the rumen microbiota involved in the chlorpyrifos degradation and the initial clue that the rumen microbes are capable of degrading chlorpyrifos. Further, the animal studies in different species with the variable levels of chlorpyrifos are also warranted to confirm the efficacy of rumen microbes in mixed syntrophy and determine the threshold capabilities of the ruminal microbes. Full article

Game-based learning approaches, particularly escape room games (ERGs), have gained increasing attention in mathematics and STEM education due to their theoretical potential to foster engagement, interest, positive attitudes, communication, teamwork, and problem-solving skills. This paper presents a theoretical and design-based conceptual analysis of educational ERGs (EERGs) within mathematics education, where issues of interest, engagement, negative attitudes and limited real-world relevance remain persistent challenges. This paper aims to develop a socio-constructivist conceptual and design framework for EERGs by synthesizing relevant educational theory, research literature and professional game design practice. Based on literature and design-informed analysis, the paper proposes a classification of puzzle types and structural configurations, analyzing the epistemic mechanisms through which these elements are theoretically expected to foster student competencies and dispositions such as positive attitudes towards learning, collaboration, communication, problem-solving and engagement. The paper also presents an author-developed game prototype as an illustrative design heuristic derived from the conceptual framework and professional practice. Finally, the paper discusses theoretical advantages and limitations considering methodological, organizational, technical and pedagogical aspects. The contribution of this study comes from an interdisciplinary understanding of EERGs, and a conceptual and design framework intended to inform future design-based and empirical research on EERGs. Full article

Background: This study evaluated morphological and functional differences among eyes with retinitis pigmentosa (RP) classified according to fundus autofluorescence (FAF) patterns. Methods: A total of 146 eyes from 73 patients with RP were analysed. Based on FAF imaging, eyes were classified as having regular hyperautofluorescent rings (n = 23), irregular rings (n = 76), or absent rings (n = 47). Participants underwent best-corrected visual acuity (BCVA), contrast sensitivity, 10–2 and 30–2 static perimetry, multifocal electroretinography (mfERG), and optical coherence tomography (OCT). FAF morphometrics included ring diameters and area. Results: Eyes with a regular FAF ring demonstrated significantly better visual function than those with irregular or absent rings, including higher BCVA (p < 0.001 and p = 0.001) and greater contrast sensitivity (both p < 0.001). The mfERG amplitude density in the first ring was higher in regular than irregular FAF patterns (p = 0.034). Eyes with irregular FAF showed more advanced visual field loss, with lower mean deviation on 10–2 (p = 0.042) and 30–2 perimetry (p = 0.027). In the regular-ring group, the ellipsoid zone was predominantly intact (p = 0.012). The hyperautofluorescent ring area correlated positively with mfERG amplitude density in the first and second rings (Rs = +0.573, p = 0.016; Rs = +0.736, p = 0.001) and with macular volume (Rs = +0.667, p = 0.003). Conclusions: FAF patterns reflect central retinal functional and structural impairment in RP. Therefore, incorporating FAF imaging into the diagnostic algorithm is valuable for monitoring disease progression. Full article

Background: Hypothermic oxygenated perfusion (HOPE) has emerged as a promising preservation strategy before liver transplantation, mitigating ischemia–reperfusion injury and improving graft function, especially in marginal grafts and donors after cardiac death. Methods: This is a prospective monocentric study; 34 HOPE-treated liver grafts were enrolled and analyzed through histopathology and RT-PCR to assess endothelial-related gene expression and its correlation with post-transplant outcome. The aim of the present study was to assess the relationship between the expression of genes related to vascular activation and homeostasis and post-transplant clinical characteristics. Results: Expression of SMA and TGF-β1 was significantly associated with arteriolar myointimal thickening of the graft (p = 0.007 and 0.068). Higher expression of SMA, ERG, and TGF-β1 was correlated with a shorter post-operative intensive care stay (p = 0.070, p = 0.010 and p = 0.029, respectively), particularly with post-transplant acute kidney injury. Conclusions: These findings highlight the role of endothelial activation and vascular homeostasis for an early recovery after liver transplantation, posing an important issue for healthcare systems as well, and suggesting molecular markers for graft assessment and risk stratification. Full article

Background/Objectives: The correlation between in vivo morphological and functional changes in the degenerating retina in a large animal model of retinitis pigmentosa (RP) has not been characterized longitudinally. Herein, spectral domain optical coherence tomography (SD-OCT) was used to monitor the dynamic morphological changes in the Pro23His rhodopsin transgenic (TgP23H) pig model of RP and was correlated with electroretinography (ERG) in the rapid, early phase of photoreceptor degeneration. Methods: TgP23H and wild-type (WT) hybrid pig littermates at the ages of postnatal days 30 (P30), P60, and P90 were studied. The thickness of different retinal layers was quantified using SD-OCT and compared with histology. Retinal function was evaluated with ERG at corresponding time points. Results: In the WT pigs, retinal morphology on SD-OCT was consistent throughout the observation period. In the TgP23H pigs, the retinal thickness decreased significantly from P30 to P90. Moreover, the relative intensity of the ellipsoid zone (EZ) progressively decreased, while the intensity of the interdigitation zone–retinal pigment epithelium (IZ-RPE) progressively increased during this period. Morphological changes in SD-OCT corresponded with histology, as well as the progressively decreased amplitude of the ERG photopic a- and b-waves in the TgP23H pigs. Conclusions: Retinal degeneration can be quantified using SD-OCT by measuring retinal thickness and the intensity of the EZ and IZ-RPE bands in the TgP23H pig. The SD-OCT results correspond with the histologic and ERG assessments of retinal degeneration. These data provide a foundation for future preclinical studies investigating potential new therapeutic strategies in a large animal model of retinitis pigmentosa. Full article

Background: Full field electroretinography (ERG) is an essential tool for assessing retinal function and diagnosing retinal diseases. In recent years, mydriasis-free handheld ERG devices have emerged as portable, non-invasive alternatives to traditional ERG systems. Their main application has been in the screening and monitoring of diabetic retinopathy (DR), particularly in settings with limited access to standard ERG equipment and in pediatric populations where conventional testing may be difficult to perform. This review aims to evaluate the current evidence on handheld ERG devices in ocular diseases, with a focus on their reliability, diagnostic accuracy, and inherent limitations. Methods: A review was conducted to identify studies evaluating handheld ERG devices in diverse clinical settings, including retinal diseases, DR, pediatric populations, and conditions such as glaucoma. A comprehensive search of the Pubmed and Embase databases was performed for studies published up to December 2024. Search terms included “mydriasis free ERG”, “handheld ERG”, “portable ERG”, “RETeval”, “healthy subjects”, “retinal diseases”, “diabetic retinopathy”, “glaucoma”, and “pediatric diseases”, as well as relevant MeSH terms and synonyms. Case reports, conference abstracts, non-human studies, and letters were excluded. After screening titles and abstracts, additional studies not meeting the inclusion criteria were excluded. Of 279 records that were initially identified, 55 met the eligibility criteria and were included in the final review. Results were synthesized narratively due to heterogeneity in the study design, populations, and outcomes. Findings were organized thematically according to clinical context. Results: A total of 57 studies were included in the review: 19 conducted in healthy subjects, 13 in diabetic retinopathy, eight in selected retinopathies, eight in glaucoma, and 14 in pediatric cohorts. Five studies overlapped between groups due to shared populations or study designs. No meta-analysis was performed due to heterogeneity in study design and outcome measures; therefore, findings were summarized narratively across disease categories. Handheld ERG devices have been evaluated in healthy subjects, patients with DR, other retinal pathologies, glaucoma and pediatric cohorts. Evidence indicates that these devices provide a rapid, non-invasive assessment of retinal function and are particularly valuable where conventional ERG is difficult to implement and potentially well-suited for screening purposes. They show good sensitivity and reasonable specificity for detecting functional changes, making them suitable for screening purposes. However, limitations exist: reduced performance in detecting early-stage disease and cone dysfunction, risk of false positives, and variability in waveform morphology and amplitude compared with traditional ERG systems. Reproducibility challenges are noted among pediatric patients and individuals with poor fixation or unstable eye movements. These discrepancies highlight the need for establishing robust normative datasets for both healthy subjects and specific disease states. Conclusions: Handheld ERG devices provide a rapid, accessible and user-friendly option for retinal assessment. While not a replacement for conventional ERG, they serve as complementary tools, particularly in early disease and in contexts where standard testing is less feasible. Further research is required to refine testing protocols, improve diagnostic accuracy, and validate their application across a broader spectrum of ocular diseases. Full article

Background/Objectives: The annual ~36,000 prostate cancer (PCa) deaths represent a large clinical unmet need and a call for deeper understanding of PCa metastasis. Epithelial–mesenchymal-transition (EMT) has been used to model metastatic behaviors in numerous cancers including PCa. One hallmark of EMT is cell cycle suppression, but how EMT impacts PCa proliferation remains unclear primarily due to the lack of appropriate models. Methods: We transiently induced Snail1 (SNAI1) expression, an EMT driver expressed in PCa, at physiological levels in three PCa cells lines, C4-2B, 22Rv1, and DU145. We used RNA-seq, ChIP-Seq, bioinformatics, qRT-PCR, shRNA, and immunoblotting to identify mechanisms of Snail1-driven inhibition of proliferation. Results: Snail1 suppressed proliferation and G2/M cell cycle progression, without affecting cell death. Mechanistically, Snail1 upregulated expression of CEBPγ, ERG1, FOXO1, cyclin G1, p21, stress genes SESN3 and SOD3, apoptotic programmers Puma, Bax, and Noxa, and senescence-related laminB1, and downregulated Ki67, cyclins A2 and B2. ChIP-Seq data identified Snail1 direct binding to p21, cyclin B2 and G1, EGR1, and CEPBγ promoters. EGR1 induced FOXO1, and EGR1 was required for Snail1-induced SOD3 and Puma, and suppression of Caspase 3 to prevent apoptosis. The EGR1/FOXO1 axis induced BAX, Noxa, and SESN3. CEBPγ was required for Snail1 induction of Lamin B1 to block Snail1-induced senescence. Conclusions: We identified three new major downstream targets of Snail1 that improve our understanding of the role of EMT in limiting stress signaling, apoptosis, and senescence during cell cycle suppression to create a vulnerability for therapeutic targeting. Full article

Background: Case marking serves as a crucial cue in sentence processing, enabling the prediction of upcoming arguments, thematic roles, and event structure. Cross-linguistic studies have revealed language-specific variations in case processing, with differences observed between nominative–accusative and ergative languages, albeit with limited data from the latter. Objective: To this end, we investigated case processing in Hindi compound light verb constructions, leveraging its split-ergative system. Methods: An ERP study was conducted with twenty-four native Hindi speakers, wherein the subject case (ergative or nominative) either matched or mismatched with the aspect marking on the light verb (perfective or imperfective). Results: The results revealed distinct ERP effects depending upon the subject case: a P600 effect for ergative case violations at the imperfective light verb and a biphasic N400-P600 effect for nominative case violations at the perfective light verb. Conclusions: These findings suggest underlying neurophysiological differences in the processing of ergative versus nominative case alignment within light verb structures. Moving forward, a closer examination of structure-specific neurophysiological variation can help bridge the gap between typological distributions and their neural underpinnings. Full article

This study evaluated the early structural and functional effects of combined citicoline and coenzyme Q10 (CoQ10) (CitiQ10) treatment in a laser-induced ocular hypertension (OHT) model in Swiss albino mice, focusing on retinal inflammation and neuroprotection. Sixty male CD-1 mice were assigned to four groups: vehicle, CitiQ10, OHT, and OHT + CitiQ10. OHT was induced by laser photocoagulation of limbal and episcleral veins, and CitiQ10 was administered orally starting 15 days before induction. Intraocular pressure (IOP) was measured by rebound tonometry, retinal structure was assessed by spectral domain optical coherence tomography (SD-OCT), and function was evaluated using full-field electroretinography (ffERG). At 3 days post-induction, OHT eyes exhibited significant retinal nerve fiber layer (RNFL) thickening, increased vitreous particles, and early functional impairment, particularly reduced scotopic b-wave and oscillatory potentials. CitiQ10 treatment mitigated these changes, reducing vitreous particles, moderating RNFL alterations, and not exhibiting significant changes in ERG amplitudes. At 7 days post-induction, structural and functional deficits persisted but were less pronounced in treated eyes. These findings suggest that CitiQ10 treatment may attenuate early retinal damage in glaucoma, with OCT and ffERG serving as reliable monitoring tools, supporting the therapeutic potential of this approach in early stage disease. Full article

(1) Background: Modifications of histone methylation could alter chromatin structure and thereby have an impact on gene expressions. (2) Methods: To investigate whether ORY-1001 delay retinal photoreceptor degeneration, rd10 mice were intraperitoneally injected with ORY-1001 (0.075 mg/kg) every second day from the 14th to the 24th day after birth. Full-field electroretinogram detection (ff ERG), optical coherence tomography (OCT), visual behavioral testing, retinal tissue morphology observation, and protein expression detection experiments were performed on the 25th day. Simultaneously, ATAC-seq and RNA-seq were used to test the mice’s retinal tissues, and metabolomics detection and quantitative real-time polymerase chain reaction (qRT-PCR) were carried out. (3) Results: Compared with the rd10 group, in the treatment group, the function in the electroretinogram response and the visual behavioral responses were improved, the nuclear layer morphology of retinal tissue was reserved more, and the protein expression of H3K4me2 and CoREST was increased. Conjoint analysis of our ATAC-seq and RNA-seq results showed that chromatin accessibility was changed, as was gene expression which was involved in metabolism changes. In addition, the effector gene in the retina was Gnat1. (4) Conclusions: ORY-1001 delays retinal photoreceptor degeneration by inhibiting H3K4me2 demethylation in rd10 mice, which suggests that ORY-1001, as a novel epigenetic modifier, has potential for treating RP. Full article

Background: Alcohol use disorder is a common condition with high morbidity and mortality and no highly effective treatments. Achieving and maintaining abstinence is necessary or desired for many persons with AUD, but is difficult due to the nature of the condition. Pharmacologic inhibition of the enzyme ALDH2, which increases levels of the substrate acetaldehyde when alcohol is imbibed, can serve as a powerful enforcer of efforts to remain abstinent. Disulfiram is an approved ALDH2 inhibitor via its active metabolite DETC-MeSO, but has many limitations, including numerous adverse effects, hepatotoxicity, oral administration, and unpredictable mechanistic activity. Methods: SOPH-110S, an analog of DETC-MeSO, was evaluated in a series of experiments to assess mechanism, pharmacokinetics in male beagle dogs, cardiovascular safety in telemeterized male beagle dogs, selectivity, off-target activity, CYP inhibition, and proof of mechanism in a rat model that included dosing and alcohol challenge followed by analysis of liver ALDH2 inhibition. Results: SOPH-110S showed high potency with a comparable IC₅₀ vs. positive controls and no physiologically relevant off-target binding in an 84-target panel. It did not inhibit or induce any major CYP enzymes or meaningfully inhibit the hERG channel. After 10 days’ dosing in rats, followed by administration of alcohol, SOPH-110S was a highly potent, dose-dependent inhibitor of ALDH2, comparable to DETC-MeSO. No cardiovascular safety concerns were found at multiples above expected clinical doses. Conclusions: The preclinical data support further clinical study of SOPH-110S as a potential ALDH2 inhibitor treatment for AUD. The FDA approved the IND to conduct a first-in-man phase 1 study in September 2025. Full article