Search Results (290)

Human cytomegalovirus (CMV) remains a significant infectious complication after kidney transplantation, reflecting gaps in the understanding of the molecular and immunological mechanisms regulating the transition from latency to productive infection. Following primary infection, CMV establishes lifelong latency in hematopoietic and myeloid lineage cells, maintained by viral chromatin repression and robust CMV-specific immune surveillance. CMV reactivation is associated with graft dysfunction, increased risk of rejection, opportunistic infections, and reduced patient survival. In kidney transplantation, CMV reactivation is driven by the interplay between tissue injury, inflammation, and immunosuppression. Ischemia–reperfusion injury and peri-operative stress produce reactive oxygen species, DNA damage, and pro-inflammatory cytokines (e.g., TNF-α, IL-6), which activate transcription factors such as NF-κB and AP-1. These factors regulate the CMV major immediate-early promoter (MIEP), thereby triggering lytic viral gene expression. At the same time, immunosuppressive therapies impair antiviral immune surveillance and, in some cases, induce cytokine release, potentially contributing to the pro-inflammatory environment that favors viral reactivation. In this review, we summarize current molecular and immunologic mechanisms governing CMV latency and reactivation with a focus on how immunosuppressive strategies and injury-associated pathways converge to promote CMV reactivation. We also discuss implications of risk stratification and the development of targeted therapeutic strategies to prevent CMV reactivation in kidney transplant recipients (KTRs). Full article

Background: The timing and efficacy of Achilles tendon lengthening (ATL) in Duchenne muscular dystrophy (DMD) remain controversial because indiscriminate surgery can accelerate ambulation loss. Case Description: This report presents a 5-year longitudinal comparative analysis (2021–2026) of monozygotic twins with identical genetic backgrounds (DMD exon 30–43 deletion) who received comparable rehabilitation and pharmacological management, including concurrent gene therapy in 2025. Twin A was managed conservatively with orthosis and subsequent serial casting for progressive equinus contracture, whereas Twin B underwent early bilateral ATL during transition to the non-ambulatory phase. Despite a temporary postoperative decline, Twin B demonstrated a more stable longitudinal motor trajectory, outperforming Twin A in gross motor function (Gross Motor Function Measure-88: 38.60% vs. 32.85% in 2026) by preserving residual standing and crawling dimensions. Longitudinal KIDSCREEN-52 assessments revealed a clinically meaningful improvement in psychological well-being in Twin B (+10.9 points) relative to Twin A. Conclusions: This single-pair twin case serves as a hypothesis-generating observation, highlighting a potential longitudinal association between early surgery and attenuated progressive motor decline within a multi-disciplinary care regimen. Given highly variable psychosocial outcomes, these trends cannot be directly attributed to surgery alone. When evaluating such orthopedic interventions, clinical decisions may benefit from looking beyond immediate gait metrics toward broader, long-term functional trends, though the relative contributions of concurrent therapies remain to be elucidated. Full article

Chemical euthanasia protocols are routinely applied across zebrafish developmental stages, but the effects of formulation, time exposure, and developmental stage remain unclear and could introduce variability in transcriptional results and interfere with interlaboratory reproducibility of molecular endpoints. Wild-type AB zebrafish were exposed at three developmental windows (6 hpf, gastrulation; 30 hpf, pharyngula; 100 hpf, pre-feeding larva) to three operational euthanasia formulations (clove oil 0.1% v/v, tricaine/MS-222 1 g/L, or lidocaine 1 g/L), for 3, 10, or 25 min. Expression of ten genes covering immediate-early activation, cellular stress, metabolism, neuroendocrine signalling, apoptosis, and inflammation was quantified by qPCR. Expression responses were analysed using a three-way factorial framework including the developmental phase, formulation, and exposure time. The developmental phase explained substantial developmental context in several genes. The Phase × Treatment interaction was significant after global FDR correction for nine of ten genes, whereas treatment main effects did not provide a stable cross-stage ranking of formulations. Descriptively, gene expression varied across formulations and stages, with several Phase III markers showing positive shifts, but no operational formulation showed universally consistent effects after multiple-testing correction, while effect-size magnitudes should be interpreted cautiously. Acute transcriptional responses to operational chemical euthanasia formulations in zebrafish embryos and larvae were context-dependent. Developmental stage, rather than a universal formulation effect, emerged as the most consistent modulator. Because euthanasia efficacy and non-recovery were not experimental endpoints, these transcriptional data do not identify a best formulation for each developmental phase. These results support stage-aware reporting of euthanasia conditions. Full article

Background/Objectives: Antidepressant treatment response is highly variable, and CYP2D6 metabolizer phenotype has been proposed as a contributor to this variability. It was examined whether CYP2D6 metabolizer phenotype is associated with real-world antidepressant treatment outcomes in a large population-based cohort. Methods: Using genetic and longitudinal primary care prescription data from the UK Biobank, we evaluated associations between CYP2D6 metabolizer phenotype and prescription-based proxies of treatment outcomes, including discontinuation, switching, and side effects. Analyses were stratified by antidepressant and adjusted for demographic covariates. Results: Among 26,957 individuals of European ancestry prescribed CYP2D6-metabolized antidepressants, reduced metabolic capacity was significantly associated with early discontinuation of paroxetine (N = 5718), venlafaxine (N = 2327), and mirtazapine (N = 3340). For paroxetine, poor metabolizers had higher odds of discontinuation compared with normal metabolizers and, among discontinuers, were more likely to stop immediately rather than later. Similar early discontinuation signals were observed for venlafaxine, with intermediate metabolizers showing increased risk. Mirtazapine also demonstrated increased odds of early discontinuation among poor metabolizers. No significant association was observed for fluoxetine. Associations with switching were limited, and no significant associations were detected for side effects. Conclusions: CYP2D6 variation appears to primarily influence early antidepressant discontinuation within the first 30 days of treatment, particularly for paroxetine, venlafaxine, and mirtazapine, rather than treatment switching or side effects. These findings provide observational support relevant to drug-specific gene interactions and suggest a role for CYP2D6-guided prescribing in clinical practice, notably in the first 30 days of antidepressant treatment. Full article

Background: Late-onset preeclampsia (LO-PE) is the most prevalent clinical phenotype of preeclampsia and, although traditionally considered less strongly associated with placental dysfunction than early-onset disease, increasing evidence supports the presence of relevant placental alterations. The extracellular matrix (ECM) is a key regulator of villous architecture, tissue mechanics, trophoblast behavior, vascular remodeling, and angiogenesis. This study aimed to characterize ECM remodeling in placentas from women with LO-PE. Patients and Methods: A prospective observational study was conducted in 111 pregnant women, including 68 with LO-PE and 43 healthy controls. Placental samples were collected immediately after delivery. Gene expression of elastogenesis-related markers, cross-linking enzymes, fibrillar collagens, matrix-remodeling regulators, and endothelial–matrix signaling molecules was assessed by RT-qPCR. Protein expression was evaluated by immunohistochemistry. Differences between groups were analyzed using non-parametric tests with Benjamini–Hochberg correction, and correlations among ECM markers were explored using Spearman analysis. Results: LO-PE placentas showed significantly increased expression of tropoelastin (TE), fibulin-4 (FBLN-4), fibulin-5 (FBLN-5), fibrillin-1 (FBN-1), lysyl oxidase (LOX), lysyl oxidase-like 1 (LOXL-1), collagen type I (COL-I), collagen type III (COL-III), and matrix metalloproteinase-2 (MMP-2) at both gene and protein levels. Conversely, gene and protein expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) and epidermal growth factor-like domain 7 (EGFL7) showed a marked decrease in the placentas of pregnant women with LO-PE. These findings indicate enhanced elastogenesis, increased matrix cross-linking, greater fibrillar collagen deposition, and an imbalance in matrix turnover. Correlation analysis further suggested that, although the FBLN-4/FBLN-5 axis remained preserved, LO-PE placentas displayed partial disruption of the broader ECM transcriptional network. Conclusions: LO-PE placentas exhibit a coordinated but dysregulated ECM remodeling phenotype involving elastic, collagenous, proteolytic, and endothelial–matrix regulatory pathways. These alterations support ECM remodeling as a relevant biological feature of LO-PE placental pathophysiology. Full article

The Sugars Will Eventually be Exported Transporters (SWEET) family plays a crucial role in the carbohydrate distribution, phloem loading, and stress response of plants, yet the evolutionary characteristics and functional diversification of SWEET genes in the endangered timber species Phoebe bournei (Hemsl.) Yen C. Yang remain largely unexplored. In this study, 21 PbSWEET genes were identified and classified into four subfamilies (A–D). Subfamily A exhibited a unique lineage expansion, mainly driven by tandem and segmental duplications. The nonsynonymous-to-synonymous substitution ratio (Ka/Ks) values of all duplicate gene pairs were all less than 1, indicating a strong selective suppression effect; consistent with this evolutionary constraint, the majority of PbSWEET proteins harbor the conserved Medicago truncatula Nodulin 3/saliva (MtN3_slv) domain, with only a few exceptions lacking a complete version. Promoter and hormone response analyses revealed that under abscisic acid (ABA) stress, PbSWEET4 exhibited an immediate burst, whereas PbSWEET10 showed a delayed burst. Physiological data indicated that soluble sugars may be more dominant osmolytes than proline (Pro), a pattern that points to a potential carbon-centric regulatory strategy. PbSWEET4 showed an early burst before sugar/oxidative peaks, suggesting a possible non-canonical signaling role, whereas PbSWEET10 exhibited a late increase coinciding with sugar/malondialdehyde (MDA) peaks, suggesting potential involvement in sugar redistribution. Under methyl jasmonate (MeJA) treatment, PbSWEET10 was rapidly induced, yet sugar accumulation occurred only at 24 h, a temporal decoupling that suggests a possible transcription–metabolism decoupling. Collectively, these correlative patterns point to a possible dual-wave transcriptional mechanism and nominate PbSWEET10 as a candidate for stress response, though these inferences require functional validation. Full article

The aim of this study was to characterize the coordinated dynamics of the mammary microbiome, antibiotic resistance genes (ARGs), and mobile genetic elements (MGEs) across the dry period, calving, and early lactation. The mammary microbiome undergoes substantial ecological changes across these stages, yet the coordinated dynamics of microbial composition, ARGs, and MGEs remain poorly understood. Here, shotgun metagenomic sequencing was performed on mammary secretion samples collected before dry-off (BM), immediately after calving (ACM), and one month postpartum (AM). The mammary microbiome exhibited a clear “exposure–bottleneck–reassembly” trajectory. BM was characterized by high microbial diversity and the enrichment of environmentally associated taxa, whereas ACM displayed a pronounced immunological bottleneck with markedly reduced microbial diversity and network complexity. During AM, microbial communities partially recovered but remained distinct from the BM state, indicating persistent ecological restructuring after calving. ARGs and MGEs showed parallel dynamics, with broad resistome and mobilome diversity in BM, a sharp contraction in ACM, and a selective re-expansion in AM. Network analysis further revealed maximal ecological complexity in BM, increased ARGs/MGEs connectivity in ACM, and partial stabilization in AM. These findings demonstrate that host physiological transitions, together with dry cow therapy (DCT), drive the coordinated remodeling of the mammary microbiome, resistome, and mobilome across the dry period. Full article

While early embryonic loss affects the conception rate in lactating cows, the underlying mechanisms remain unknown. Here, we examined whether the developmental morphokinetics and transcriptomic profiles of cleaved embryos are associated with developmental competence. Developing bovine embryos were produced in vitro, and their morphokinetics were monitored through 190 h using a time-lapse system. The proportion of embryos that developed to the blastocyst stage was lower following abnormal cleavage, i.e., reverse, direct, or unequal, relative to normally cleaved embryos (p < 0.05). In a second set of experiments, exploratory RNA-seq analysis was performed on first-cleaved embryos, which were individually collected immediately after the first division; embryos were defined by the time-lapse system as normally, directly, or unequally cleaved (n = 6 per group), or reverse-cleaved (n = 5). Analysis revealed 672 genes that were differentially expressed between normally and abnormally cleaved embryos (adjusted p < 0.05). Abnormally cleaved embryos differed in pathways associated with energy production and metabolism. The most profound difference in gene expression (n = 632) was between unequally and normally cleaved embryos, mainly in genes affiliated with the oxidative phosphorylation pathway. These findings support the concept that the morphokinetic pattern of early embryonic cleavage is associated with developmental competence. We therefore suggest that the observed differential expression profiles in abnormally cleaved embryos might be involved in the mechanism underlying early embryonic loss. Full article

Peripheral nerve ischemia–reperfusion injury is considered to contribute to sensory disturbances that impair quality of life in patients with diabetic neuropathy and chemotherapy-induced neuropathy. However, the spinal mechanisms underlying these disturbances remain unclear, partly due to the lack of established animal models and evaluation systems. In the present study, we used a rat hindlimb ischemia–reperfusion model and in vivo extracellular recording to examine bidirectional changes in neuronal activity in the spinal dorsal horn. Ischemia was induced by tightly binding the rat ankle with a rubber band, followed by reperfusion. Behavioral analysis showed a significant increase in hindlimb licking behavior after reperfusion, indicating the development of sensory disturbance-like responses. Extracellular recordings from superficial dorsal horn neurons showed diverse patterns of spontaneous firing and responses to mechanical stimulation, with both hypersensitive and desensitized responses. Furthermore, mRNA expression levels of immediate early genes (Egr1, Egr3, and Fos) were upregulated in the spinal cord after reperfusion. These results suggest that this ischemia–reperfusion model reproduces complex neuronal responses relevant to peripheral neuropathy and provides a useful evaluation system for evaluating both increased and decreased neural activity. This approach may contribute to elucidating the mechanisms of sensory disturbances and to the development of new treatments for neuropathic conditions. Full article

During fermentation in stirred-tank bioreactors (STBR), filamentous fungi are frequently exposed to hypoxic conditions. However, their responses, especially short-term ones (≤6 h), remain unclear. In this study, we performed a short-term multi-omics profiling in an Aspergillus oryzae hyphal dispersion mutant (AGΔ-GAGΔ) during a controlled transition to hypoxia (a decrease in dissolved oxygen (DO) from 10% to ≤1%) in a 4 L STBR. In transcriptome analysis, the genes encoding mitochondrial respiratory chain Complexes I–III were transiently downregulated at 1 h from DO depletion and were then upregulated, whereas those of Complex IV were upregulated immediately at the onset of hypoxia. In relation to this respiratory remodeling, we also observed an immediate induction of an alternative oxidase (AOX) gene. However, our metabolome data showed no significant change in the ATP level. This result could be explained by the upregulation of the glycolytic genes in hypoxic cultures. Fluorescence imaging revealed a transient increase in intracellular reactive oxygen species (ROS) in hypoxia, and metabolomics data revealed a decrease in the reduced glutathione/oxidized glutathione ratio in hypoxic cultures. Deletion of the AOX gene prolonged the ROS increase. Together, these data indicate that early hypoxia triggers a transient increase in oxidative stress, mitigated by antioxidant systems and mitochondrial respiratory rebalancing including an AOX-mediated bypass. Full article

Background/Objectives: DNA methylation is a key epigenetic modification involved in regulating many cellular processes, including gene expression and the maintenance of genome stability. Ultraviolet (UV) radiation induces DNA damage in the form of pyrimidine-pyrimidone (6-4) photoproducts [(6-4)PPs] and cyclobutane pyrimidine dimers (CPDs), which can lead to mutations if not efficiently repaired. While cytosine methylation has been implicated in influencing UV-induced DNA damage formation, the effect of DNA methylation modulators such as S-adenosyl-L-methionine (SAM) and RG108 on UV damage formation and repair remains unclear. Methods: Here, using immunoslot blot assays, we investigated the effects of SAM and RG108 on UV-induced DNA damage formation and repair in human lymphoblastoid cells. Results: We found that SAM, but not RG108, rapidly suppresses the formation of both (6-4)PP and CPD, with detectable effects within minutes of exposure. Although SAM pretreatment was associated with modestly accelerated early (6-4)PP repair, this effect was accompanied by substantially lower initial damage levels. When cells were treated with SAM or RG108 immediately after UV irradiation to ensure equivalent initial damage burden, no significant differences in repair were observed for either lesion type, demonstrating that the accelerated early (6-4)PP repair reflects reduced lesion burden rather than increased intrinsic nucleotide excision repair (NER). Global 5-methylcytosine (5mC) levels remained stable following SAM or RG108 treatment and during UV damage repair, suggesting that these effects occur independently of global alterations in DNA methylation. Conclusions: Together, our findings reveal that SAM modulates UV damage susceptibility at the level of lesion formation without altering repair, highlighting a previously unrecognized role for DNA methylation modulators in regulating genome stability. Full article

Epstein–Barr virus (EBV) establishes lifelong infection in most humans, yet its biology in immunocompetent hosts is commonly framed as a binary alternation between latency and productive lytic replication. Accumulating molecular and single-cell evidence challenges this view, indicating that EBV frequently enters abortive forms of lytic reactivation that do not culminate in virion production. Here, we propose a conceptual framework in which EBV persistence is governed by feedback-regulated interactions and permissive conditions for reactivation rather than a strictly sequential life cycle. Immediate-early and early gene expression can be repeatedly induced by inflammatory signaling, cellular stress, and epigenetic changes. However, progression to viral DNA replication represents a highly functional barrier that likely requires the coordinated convergence of multiple viral and host conditions. Failure to reach this threshold arrests reactivation before late gene expression, generating a stable partial lytic state characterized by sustained immunomodulatory viral protein expression without the production of infectious particles. Immune surveillance reinforces this bottleneck by eliminating cells undergoing full lytic replication while sparing those stalled in early phases. We argue that EBV persistence reflects a dynamic equilibrium shaped by regulatory interactions between viral gene expression and host immunity, with implications for biomarker interpretation and therapeutic strategies in chronic inflammatory and autoimmune disease. Full article

Pharmacological antidepressant treatments alter the molecular and functional reactivity of stress-sensitive neural networks. However, how classical versus rapid-acting antidepressants differentially modulate acute stress-induced transcriptional responses across brain regions remains unclear. Here, we compared imipramine and ketamine in mice exposed to acute swim stress, assessing transcriptional adaptations across the frontal cortex, hippocampus, and striatum. Swim stress induced significant widespread activation of cFOS, which led to drug-specific modulations: imipramine primarily significantly dampened cortical and striatal cFOS expression, whereas ketamine preserved stress-evoked neuronal activation. In contrast, hippocampal activation was significantly robust but largely unaffected, indicating that acute antidepressant drug effects during stress coping preferentially target cortical and striatal plasticity mechanisms. In contrast, BDNF expression was altered only within the striatal region, where imipramine attenuated the stress-related increase in BDNF expression. Statistical analysis of behavioral outcomes during the swim stress confirmed a shared facilitation of active coping, yet these similar outcomes emerged from distinct molecular programs. Together, the data demonstrate that the treatment effects of the two substances diverge mechanistically, revealing cortical and striatal transcriptional signatures of classical versus rapid-acting antidepressant action. While these findings suggest potential translational relevance for understanding distinct mechanisms, further studies in humans are required to validate these signatures and their clinical implications. Full article

Apostichopus japonicus undergoes evisceration in response to adverse environmental stimuli, and its coelomocytes undergo rapid regeneration within 6–24 h to restore innate immune function. FOS, an immediate early gene, regulates cell proliferation and cycle, but its role in A. japonicus coelomocyte regeneration after evisceration is unclear. In this study, AjFOSL from A. japonicus was cloned, which harbors a 609 bp open reading frame (ORF) encoding 202 amino acids (aa) with a conserved bZIP domain and is localized on chromosome 14. It shares 58% homology with FOS from Holothuria leucospilota and Lytechinus pictus. Phylogenetic analysis revealed that AjFOSL clusters closely with FOS from Magallana gigas and Mytilus edulis. Tissue distribution analysis showed that AjFOSL was widely expressed in various tissues, with the highest expression level detected in the tentacles. Temporal expression profiling demonstrated that AjFOSL was significantly upregulated by 1.75-fold at 6 h after evisceration. After AjFOSL knockdown, the peak expression of Cyclin A, Cyclin B, and E2F was delayed and the coelomocyte number was consistently reduced compared with that in the evisceration-only group. The AjFOSL acted as an immediate early response gene and was associated with the regulation of coelomocyte regeneration by modulating the expression of cell cycle-related genes. This study provides novel insights into the molecular associations underlying coelomocyte regeneration and the evolutionary adaptation of FOS genes in echinoderms. Full article

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