Search Results (45)

Zebrafish (ZF) have gained increasing attention in developmental neuroscience due to their experimental tractability, favorable ethical profile, and translational value. However, the expanding use of the ZF model has also highlighted the need to consider species-specific differences in relation to early social and emotional development. This review adopts a comparative and ethological perspective to examine early social interactions in ZF and mammals, integrating evidence from non-altricial vertebrates and teleost species with parental care (cichlids). Selected illustrative ZF papers were discussed, while Cichlids fish were chosen as a complementary, translationally consistent subject for developmental behavioral studies. The analysis focuses on developmental stages that are relevant for behavioral phenotyping in models of neuropsychiatric conditions. Zebrafish offer multiple methodological advantages, including suitability for high-throughput experimentation and substantial genetic and neurobiological homologies with humans. Nevertheless, the absence of mother–offspring bonding limits the modeling of neurodevelopmental processes shaped by early caregiving, such as imprinting and reciprocal regulatory interactions, instead observed in cichlids. Accumulating evidence indicates that early interactions among age-matched ZF are measurable, developmentally regulated, and sensitive to environmental and experimental manipulations. Within a comparative approach, these early conspecific interactions could be analogs of early social bonding observed in altricial mammals. Rather than representing a critical limitation, such species-specific features can inform the investigation of fundamental mechanisms of social development and support the complementary use of ZF and mammalian models. A contextualized and integrative approach may therefore enhance the translational relevance of ZF-based research, particularly for the study of neurodevelopmental disorders involving early social dysfunction. Full article

Background/Objectives: Circulating tumor cells (CTCs) and large extracellular vesicles (LEVs) are key components of the liquid biopsy that provide minimally invasive access to tumor biology. A clinically relevant subset of CTCs coexpressing epithelial and immune markers (im.CTCs) has been described, yet the origin of this phenotype remains unclear. In this study, we investigated the cellular and molecular context underlying the emergence of immune marker expression on CTCs and LEVs. Methods: Using high-resolution immunofluorescence microscopy of patient-derived blood samples, we identified direct physical interactions between white blood cells (WBCs) and both im.CTCs and im.LEVs, exclusively in patients harboring im.CTCs. Results: In several cases, WBCs partially encapsulated CTCs and LEVs, and quantitative analysis revealed localized enrichment of immune membrane markers at the contact interface, distinguishing these events from random proximity. Proteomic profiling further identified CD4+ T cells as the predominant interacting immune cell type and confirmed the presence of CD45, CD3, and CD4 on the interacting CTCs and LEVs, matching their WBC counterparts. Conclusion: These findings support membrane transfer as a potential mechanism for the acquisition of immune markers by CTCs and LEVs and provide in vivo evidence of contact-dependent tumor-immune interactions in circulation with implications for immune modulation and clinical interpretation of the im.CTC phenotype. Full article

Background: Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis due to late-stage presentation and ineffective systemic therapies. Targeting the tumor microenvironment (TME) in ICC offers new therapeutic possibilities, particularly through tumor-associated macrophages (TAM), which can both promote and inhibit tumor progression. The current study utilized multi-omics analysis to characterize the gene signature of TAM and explore its therapeutic potential in ICC. Methods: Public GEO datasets provided the basis for analysis. Single-cell RNA sequencing (scRNA-seq) data from five ICCs, three adjacent non-tumorous tissues (ANTs), and four healthy liver samples were examined with Python. To validate scRNA-seq findings, bulk RNA-seq data from 27 ICC and 27 matched ANT samples were assessed using R. Differentially expressed genes were identified with adjusted p-values <0.01 and log2-fold changes >1 or <−1. CIBERSORT pipeline analyzed 22 immune cell subtypes in bulk RNA-seq data. STRING database analyzed the contribution of unique TAM-related genes to networks of protein–protein interactions. Results: TAM population demonstrated phenotypic heterogeneity exhibiting partial gene signatures of inflammatory (MS1) and anti-inflammatory (MS2) macrophages. Unique TAM-associated markers, TREM2, CD9, and PRMT10, showed variable expression within the TAM subpopulation. Bulk RNAseq analysis confirmed the scRNA-seq results, highlighting overexpression of TREM2 and CD9 in most ICC samples versus ANT. Immune cell deconvolution revealed decreased MS1 and MS2 macrophages in ICC, and alterations in adaptive immune profile, suggesting immunotolerant TME. STRING database defined TREM2-LGALS3 axis as a potential target for anti-tumor therapies. Conclusions: TAM represents a unique heterogenous population which is primarily found in ICC TME versus ANT or healthy liver tissue The non-uniform expression of unique gene signature demonstrates additional heterogeneity in the TAM subpopulation and suggests that TREM2+ TAM may be desirable targets for anti-TREM2-LGALS3 immunotherapy. Full article

Retinal laser therapy has been a mainstay for treating proliferative diabetic retinopathy, retinal vascular disease, and retinal breaks since 1961. However, conventional millisecond photocoagulation can cause permanent scarring and procedure discomfort, motivating the development of damage-sparing approaches that preserve the neurosensory retina. Clinically, panretinal photocoagulation remains effective for proliferative disease but trades off peripheral visual field and night vision. This review synthesizes development, mechanisms, and clinical evidence for laser modalities, including short-pulse selective retinal therapy (SRT), subthreshold diode micropulse (SDM), and pattern-scanning photocoagulation. We conducted a targeted narrative search of PubMed/MEDLINE, Embase, Web of Science, and trial registries (1960–September 2025), supplemented by reference list screening. We prioritized randomized/prospective studies, large cohorts, systematic reviews, mechanistic modeling, and relevant preclinical work. Pulse duration is the primary determinant of laser–tissue interaction. In the microsecond regime, SRT yields retinal pigment epithelium (RPE)-selective photodisruption via microcavitation and uses real-time optoacoustic or OCT feedback. SDM 100–300 µs delivers nondamaging thermal stress with low duty cycles and titration-based dosing. Pattern-scanning platforms improve throughput and tolerance yet remain destructive photocoagulation. Feedback-controlled SRT shows anatomic/functional benefit in chronic central serous chorioretinopathy and feasibility in diabetic macular edema. SDM can match threshold macular laser for selected DME and may reduce anti-VEGF injection burden. Sub-nanosecond “rejuvenation” lasers show no overall benefit in intermediate AMD and may be harmful in specific phenotypes. Advances in delivery, dosimetry, and closed-loop feedback aim to minimize collateral damage while retaining therapeutic effect. Key gaps include head-to-head trials (SRT vs. PDT/SDM), standardized feedback thresholds across pigmentation and devices, and long-term macular safety to guide broader clinical adoption. Full article

Background/Objectives: Human endogenous retroviruses (ERVs) are genomic sequences integrated into the human genome from ancestral exogenous retroviruses and are epigenetically silenced under normal conditions. Growing evidence has shown that they can be reactivated in human diseases such as cancers and autoimmune diseases. However, their clinical implications in colon cancer are yet to be explored. Methods: RNA-seq data were downloaded from RNA Atlas and TCGA for cell lines and tissue samples, respectively. After alignment, ERV expression was quantified against comprehensively compiled ERVs (3220). ERV expression profiles were compared between sequencing protocols, cancer and normal cells, and matched tumor and normal tissue pairs. Unsupervised clustering was used to identify ERV-defined tumor subtypes and their associations with clinical and other molecular features. ERV association with disease-specific survival (DSS) was performed using the Cox regression model. Results: PolyA and total RNA protocols were comparable in ERV expression detection. Cancer cells had significantly increased ERV expression and reactivation. Upregulated ERVs were significantly enriched in viral protein interactions with cytokine and cytokine receptors. ERV expression-defined tumor classes were significantly associated with tumor mutation burden and immuno-phenotypes such as antigen processing and presenting machinery and tumor immune infiltration score. Survival analysis identified 152 ERVs to be independently associated with DSS. Conclusions: ERV abnormal expression is common in colon cancer. The ERV-defined subtypes are associated with tumor immunity, and some ERVs are independently associated with patient outcomes. Full article

Chagas disease, caused by Trypanosoma cruzi, poses a significant public health challenge due to its widespread prevalence, limited therapeutic options, and adverse effects associated with available medications. In this study, we developed 13 novel pyrazole-imidazoline derivatives, inspired by a previously identified cysteine protease inhibitor, and evaluated their antiparasitic activity. Our in silico analyses predicted favorable physicochemical profiles and promising oral bioavailability for these derivatives. Upon phenotypic screening, we observed that these new derivatives exhibited low cytotoxicity (CC₅₀ > 100 µM) and marked efficacy against intracellular amastigotes. Derivative 1k showed high activity (IC₅₀ = 3.3 ± 0.2 µM), selectivity (SI = 73.9), and potency (pIC₅₀ = 5.4). In a 3D cardiac microtissue model, 1k significantly reduced parasite load, matching the efficacy of benznidazole (Bz) even at lower concentrations. Both 1k and Bz effectively prevented parasite recrudescence; however, neither resulted in parasite sterility under the experimental conditions employed. The combination of 1k–Bz yielded an additive interaction, highlighting its potential for in vivo combination therapy. While structural changes abolished cysteine protease inhibition, incorporating a CF₃ substituent at the para position and excluding the amino group enhanced antiparasitic activity. These findings reinforce the promise of the pyrazole-imidazoline scaffold and support further structural optimizations to develop innovative candidates for treating Chagas disease. Full article

Incoming feeder calf production potential can be predicted based on phenotypic appearance, and nutrient supply can be optimized to match each animal’s specific production profile. Tailoring the supply, quality, and quantity of nutrients to the requirements for maximum profit could further support the economic pillar of sustainable livestock farming. Feeder calves (n = 104) were categorized into the production profiles (PP 1; PP 2; PP 3). Within each PP category, the allocated pens were subsequently randomized into three diets (high-, medium-, and low-production diets). Economic important traits were measured, and a deterministic model was created to evaluate economic implications. There was a significant interaction between the incoming feeder calf production profile and diet on the profit margin, with the PP 2 calves being most profitable when fed on the medium-production diet (profit margin = 4.81%). This was in stark contrast of the profit made by PP 2 calves fed on the low- or high-production diets (profit margin = 0.21% and −2.97%, respectively). PP 3 calves made a loss on all diets; however, this loss was reduced by 14% when fed on the low- compared to the medium-production diet (profit margin = −1.45% and −1.68%, respectively). PP 1 calves were profitable on all three diets although the margin was highest on the medium-production diet. In conclusion, the medium-production diet, representing the current industry norm in South Africa, is financially suitable for feeding calves with average production potential (PP 2), whereas the loss made by calves with low production potential (PP 3) can be reduced by adjusting the feed formulation for low production. More work is required to formulate diets that will maximize the profit made by calves with above average production potential (PP 1). Full article

Hybrid necrosis in wheat is caused by an interaction between two genes, Ne1 and Ne2, that triggers the gradual death of plant tissue. This trait affects wheat breeding as the gene Ne2 is the same as the gene Lr13 for leaf rust resistance. We have built a three-marker haplotype that consists of single nucleotide polymorphism (SNP) marker information already available on genotyping arrays for the determination of the presence and absence of Ne2. In this work, test crosses of eight bread wheat varieties with known and unknown Ne1 carriers showed that six of them possessed Ne2. We analyzed a set of wheat varieties which had partial SNPs and phenotypic data, i.e., hybrid necrosis and leaf rust reactions, using Kompetitive Allele-Specific PCR (KASP) markers previously available for Ne2. The observed haplotypes of the SNP markers RAC875_c1226_652, Ra_c4397_542, and AX-110926324 perfectly matched the KASP marker variants for Ne2 and ne2. A prediction, based on these SNP haplotypes, of the distribution of Ne2 in wheat varieties, predominantly from Germany and released between 1900 and 2024, showed that breeding steadily increased the proportion of Ne2 in the German gene pool. Full article

Background/Objectives: Pharmacogenomics (PGx) has revolutionized personalized medicine, notably by predicting drug responses through the study of the metabolic genotype of drug-metabolizing enzymes. However, these genotypes rely heavily on the availability and completeness of drug metabolism information and do not account for (all) “phenoconversion” factors, like drug–drug interactions and comorbidities. To address these limitations, a more phenotypic approach would be desirable, for which pharmacometabolomics (PMx) could be useful by studying and elucidating drug metabolism in patient samples, such as blood and urine. Methods: This study explored the potential of PMx to analyze real-world drug metabolite profiles of the extensively studied drug cyclosporine (CsA) using 24-h urine samples from 732 kidney and 350 liver transplant recipients included in the TransplantLines Biobank and Cohort Study (NCT identifier NCT03272841). Detected metabolites were matched with existing information on CsA metabolism gathered through a comprehensive literature review, aiming to confirm previously reported metabolites and identify potentially unreported ones. Results: Our analyses confirmed the urinary presence of CsA and six known metabolites. Additionally, we detected three known metabolites not previously reported in urine and identified one unreported metabolite, potentially suggesting the involvement of glutathione conjugation. Lastly, the observed metabolic patterns showed no notable differences between kidney and liver transplant recipients. Conclusions: Our findings demonstrate the potential of PMx to enhance the understanding of drug metabolism, even for well-studied compounds such as CsA. Moreover, this study highlights the value of PMx in real-world drug metabolism research and its potential to complement PGx in advancing personalized medicine. Full article

Major depressive disorder (MDD) exhibits notable sex differences in prevalence and clinical and neurobiological manifestations. Though the relationship between peripheral inflammation and MDD-related brain changes is well studied, the role of sex as a modifying factor is underexplored. This study aims to assess how sex influences brain and inflammatory markers in MDD. We utilized voxel-based and surface-based morphometry to analyze gray matter (GM) structure, along with GM-based spatial statistics (GBSS) to examine GM microstructure among treatment-naive patients with depression (n = 174) and age-matched healthy controls (n = 133). We uncovered sex-by-diagnosis interactions in several limbic system structures, the frontoparietal operculum and temporal regions. Post hoc analyses revealed that male patients exhibit pronounced brain abnormalities, while no significant differences were noted in females despite their higher depressive scores. Additionally, heightened inflammation levels in MDD were observed in both sexes, with sex-specific effects on sex-specific brain phenotypes, particularly including a general negative correlation in males. Intriguingly, mediation analyses highlight the specific role of the parahippocampal gyrus (PHG) in mediating interleukin (IL)-8 and depression in men. The findings suggest that in clinical practice, it would be beneficial to prioritize sex-specific assessments and interventions for MDD. This includes recognizing the possibility that male patients may experience significant brain alterations, especially when identifying male patients who may underreport symptoms. Possible limitations encompass a small sample size and the cross-sectional design. In future research, the incorporation of longitudinal studies or diverse populations, while considering illness duration, will enhance our understanding of how inflammation interacts with brain changes in depression. Full article

Lamina cribrosa (LC) cells play an integral role in extracellular matrix remodeling and fibrosis in human glaucoma. LC cells bear similarities to myofibroblasts that adopt an apoptotic-resistant, proliferative phenotype, a process linked to dysregulation of tumor suppressor-gene p53 pathways, including ubiquitin-proteasomal degradation via murine-double-minute-2 (MDM2). Here, we investigate p53 and MDM2 in glaucomatous LC cells. Primary human LC cells were isolated from glaucomatous donor eyes (GLC) and age-matched normal controls (NLC) (n = 3 donors/group). LC cells were cultured under standard conditions ± 48-h treatment with p53-MDM2-interaction inhibitor RG-7112. Markers of p53-MDM2, fibrosis, and apoptosis were analyzed by real-time polymerase chain reaction (qRT-PCR), western blotting, and immunofluorescence. Cellular proliferation and viability were assessed using colorimetric methyl-thiazolyl-tetrazolium salt assays (MTS/MTT). In GLC versus NLC cells, protein expression of p53 was significantly decreased (p < 0.05), MDM2 was significantly increased, and immunofluorescence showed reduced p53 and increased MDM2 expression in GLC nuclei. RG-7112 treatment significantly increased p53 and significantly decreased MDM2 gene and protein expression. GLC cells had significantly increased protein expression of αSMA, significantly decreased caspase-3 protein expression, and significantly increased proliferation after 96 h. RG-7112 treatment significantly decreased COL1A1 and αSMA, significantly increased BAX and caspase-3 gene expression, and significantly decreased proliferation in GLC cells. MTT-assay showed equivocal cellular viability in NLC/GLC cells with/without RG-7112 treatment. Our data suggests that proliferation and the ubiquitin-proteasomal pathway are dysregulated in GLC cells, with MDM2-led p53 protein degradation negatively impacting its protective role. Full article

Background: Polymorphism rs1049434 characterizes the nonsynonymous exchange of adenosine (A) by thymidine (T) in the gene for monocarboxylate transporter 1 (MCT1). We tested whether T-allele carriers of rs1049434 demonstrate increased accumulation of markers of metabolic strain. Methods: Physically active, healthy, young male subjects (n = 22) conducted a power-matched one-legged cycling exercise to exhaustion. Metabolic substrates in capillary blood, selected metabolic compounds, and indices for the slow oxidative phenotype of vastus lateralis muscle were quantified in samples collected before and after exercise. The genotypes of the rs1049434 polymorphism were determined with polymerase chain reactions. Results: One-legged exercise affected the concentration of muscle metabolites entering the tricarboxylic acid cycle, such as acetyl-co-enzyme A (+448%) and acetyl-L-carnitine (+548%), muscle glycogen (−59%), and adenosine monophosphate (−39%), 30 min post-exercise. Exercise-related variability in the muscular concentration of glycogen, long-chain acyl co-enzyme As and a triglyceride, nicotinamide adenine dinucleotide (NADH), and adenosine monophosphate (AMP) interacted with rs1049434. T-allele carriers demonstrated a 39% lesser reduction in glycogen after exercise than non-carriers when NADH increased only in the non-carriers. Muscle lactate concentration was 150% higher, blood triacyl-glyceride concentration was 53% lower, and slow fiber percentage was 20% lower in T-allele carriers. Discussion: The observations suggest a higher anaerobic glycolytic strain during exhaustive exercise and a lowered lipid handling in T-allele non-carriers. Full article

Vertical transmission of metabolic constituents from mother to child contributes to the manifestation of disease phenotypes in early life. This study probes the vertical transmission of metabolites from mothers to offspring by utilizing machine learning techniques to differentiate between true mother–child dyads and randomly paired non-dyads. Employing random forests (RF), light gradient boosting machine (LGBM), and logistic regression (Elasticnet) models, we analyzed metabolite concentration discrepancies in mother–child pairs, with maternal plasma sampled at 24 weeks of gestation and children’s plasma at 6 months. The propensity of vertical transfer was quantified, reflecting the likelihood of accurate mother–child matching. Our findings were substantiated against an external test set and further verified through statistical tests, while the models were explained using permutation importance and SHapley Additive exPlanations (SHAP). The best model was achieved using RF, while xenobiotics were shown to be highly relevant in transfer. The study reaffirms the transmission of certain metabolites, such as perfluorooctanoic acid (PFOA), but also reveals additional insights into the maternal influence on the child’s metabolome. We also discuss the multifaceted nature of vertical transfer. These machine learning-driven insights complement conventional epidemiological findings and offer a novel perspective on using machine learning as a methodology for understanding metabolic interactions. Full article

Fetal alcohol spectrum disorders (FASD) are leading causes of neurodevelopmental disability. The mechanisms by which alcohol (EtOH) disrupts fetal brain development are incompletely understood, as are the genetic factors that modify individual vulnerability. Because the phenotype abnormalities of FASD are so varied and widespread, we investigated whether fetal exposure to EtOH disrupts ribosome biogenesis and the processing of pre-ribosomal RNAs and ribosome assembly, by determining the effect of exposure to EtOH on the developmental expression of 18S rRNA and its cleaved forms, members of a novel class of short non-coding RNAs (srRNAs). In vitro neuronal cultures and fetal brains (11–22 weeks) were collected according to an IRB-approved protocol. Twenty EtOH-exposed brains from the first and second trimester were compared with ten unexposed controls matched for gestational age and fetal gender. Twenty fetal-brain-derived exosomes (FB-Es) were isolated from matching maternal blood. RNA was isolated using Qiagen RNA isolation kits. Fetal brain srRNA expression was quantified by ddPCR. srRNAs were expressed in the human brain and FB-Es during fetal development. EtOH exposure slightly decreased srRNA expression (1.1-fold; p = 0.03). Addition of srRNAs to in vitro neuronal cultures inhibited EtOH-induced caspase-3 activation (1.6-fold, p = 0.002) and increased cell survival (4.7%, p = 0.034). The addition of exogenous srRNAs reversed the EtOH-mediated downregulation of srRNAs (2-fold, p = 0.002). EtOH exposure suppressed expression of srRNAs in the developing brain, increased activity of caspase-3, and inhibited neuronal survival. Exogenous srRNAs reversed this effect, possibly by stabilizing endogenous srRNAs, or by increasing the association of cellular proteins with srRNAs, modifying gene transcription. Finally, the reduction in 18S rRNA levels correlated closely with the reduction in fetal eye diameter, an anatomical hallmark of FASD. The findings suggest a potential mechanism for EtOH-mediated neurotoxicity via alterations in 18S rRNA processing and the use of FB-Es for early diagnosis of FASD. Ribosome biogenesis may be a novel target to ameliorate FASD in utero or after birth. These findings are consistent with observations that gene–environment interactions contribute to FASD vulnerability. Full article

Conventional 2D cultures are commonly used in cancer research though they come with limitations such as the lack of microenvironment or reduced cell heterogeneity. In this study, we investigated in what respect a scaffold-based (Matrigel™) 3D culture technique can ameliorate the limitations of 2D cultures. NGS-based bulk and single-cell sequencing of matched pairs of 2D and 3D models showed an altered transcription of key immune regulatory genes in around 36% of 3D models, indicating the reoccurrence of an immune suppressive phenotype. Changes included the presentation of different HLA surface molecules as well as cellular stressors. We also investigated the 3D tumor organoids in a co-culture setting with tumor-infiltrating lymphocytes (TILs). Of note, lymphocyte-mediated cell killing appeared less effective in clearing 3D models than their 2D counterparts. IFN-γ release, as well as live cell staining and proliferation analysis, pointed toward an elevated resistance of 3D models. In conclusion, we found that the scaffold-based (Matrigel™) 3D culture technique affects the transcriptional profile in a subset of GBM models. Thus, these models allow for depicting clinically relevant aspects of tumor-immune interaction, with the potential to explore immunotherapeutic approaches in an easily accessible in vitro system. Full article