Parkinson’s disease (PD), the second most common progressive neurodegenerative disorder, is classically defined as a motor disorder characterized by dopaminergic neuron loss in the substantia nigra and motor dysfunction. Increasing evidence, however, identifies PD as a multisystem disorder with early non-motor features, including sleep, psychiatric, and gastrointestinal disturbances, implicating the gut-brain axis. Tryptophan metabolism through serotonin, kynurenine, and indole pathways generates bioactive metabolites, many of which regulate the aryl hydrocarbon receptor (AhR). AhR is a ligand-activated transcription factor involved in xenobiotic metabolism through canonical signaling pathways; however, growing evidence supports its role in immune balance, glial responses, and barrier integrity. Altered AhR signaling may therefore connect gut dysbiosis and disrupted tryptophan metabolism to sustained, systemic and central inflammation in PD. This review examines gut dysbiosis, tryptophan metabolism, and AhR signaling as potential mechanisms underlying idiopathic PD and highlights their relevance to early diagnosis and disease-modifying therapies.
Hepatitis E virus (HEV) is a globally distributed zoonotic pathogen, spread by contaminated food and blood products, and a leading cause of acute viral hepatitis. Recent data indicate that the HEV genome contains a highly heterogeneous hypervariable region (HVR) that can tolerate extensive genomic rearrangements, especially among immunocompromised patients. These rearrangements can increase HEV replication in tissue-culture and have further been observed in HEV-infected patients. Insertions comprise either duplications of virus-derived sequences, or alternatively, host-derived sequence fragments and exhibit enrichment of specific amino acids and functional motifs. However, the molecular mechanisms driving these insertions, as well as their functional significance, remain largely unexplored. Given that sequences not required for infectivity or replication are typically rapidly eliminated in small RNA viruses such as HEV, the persistence of HVR insertions suggests a potential biological role in HEV replication and/or pathogenesis. This review summarizes our current understanding of the role of HVR insertions during HEV infection, as well as the potential mechanisms underlying these insertions. We further discuss the factors driving the selection of genomic insertions and speculate on their functional role by analyzing over 650 publicly available HEV genotype 3 genome sequences and systematically cataloging identified insertions.
Exposure to maltreatment in childhood is posited to profoundly disrupt brain development with adverse consequences for cognitive development and health across the lifespan. Here we use “brain charts” from the largest available neuroimaging database to quantify individual brain volumes relative to normative brain growth distributions in 299 children, aged 3 to 13 years, including 123 children with clinically verified maltreatment exposure. Using magnetic resonance imaging, we obtain volumes of cortical grey, total white, and subcortical grey matter and derive chart-based centiles for each child and tissue type. In our sample, children with maltreatment exposure exhibit lower mean brain centiles across tissues than unexposed children. Associations of greater maltreatment severity with lower brain centiles do not survive correction for multiple comparisons. Lower brain centiles are associated with lower intellectual ability and more behavioural problems. These findings provide evidence for widespread differences in brain structure associated with childhood maltreatment and their relevance to intellectual ability and behavioural functioning.
Transcription is inherently bursty, and burst frequency and burst size provide mechanistically informative phenotypes that are not uniquely determined by mean expression alone. Yet it remains difficult to quantify, at genome scale, how histone-modification landscapes encode these burst kinetics. Here we show that DeepBurst, a deep learning model, predicts gene-specific burst-frequency and burst-size regimes from histone-modification profiles around transcription start sites. DeepBurst uses self-attention to learn combinatorial, position-dependent predictive patterns, with training labels inferred from single-cell transcriptome data using mechanistic bursting models. Across three human cell lines and two label-inference procedures, DeepBurst achieves consistent performance under chromosome-based splits and shows strong cross-cell type generalization. Model interpretation shows that burst frequency benefits from broader chromatin context, whereas burst size depends more strongly on promoter-proximal signals. Model-constrained in silico perturbations further identify histone-profile changes predicted to shift bursting regimes. DeepBurst therefore enables genome-wide mapping from readily measurable histone-modification landscapes to hard-to-assay transcriptional bursting dynamics, while generating testable hypotheses for future perturbation studies.
Keratoconus (KC) is a multifactorial, progressive, ectatic disease of the cornea, which often manifests during puberty. The clinical phenotype includes progressive loss of stromal collagen, with emerging evidence indicating inflammation contributes to the disease pathology. In this study, we investigated the extragonadal role of follicle-stimulating hormone (FSH) in corneal stromal collagen degradation and inflammation. Using a 3D collagen hydrogel system, co-culture models, and patient-derived tears, we found the following: FSH levels were low in KC patients; FSH supplementation inhibited MAP kinase signaling, leading to decreased MMP2 activity and increased collagen accumulation; FSH increased pro-inflammatory cytokine secretion, driving macrophage polarization, migration, and tunneling nanotube formation; FSH regulated the HDAC1-miR-29b feedback loop in chromatin immunoprecipitation and overexpression studies; Gene ontology linked FSH to leukocyte adhesion and extravasation; and Motif analysis identified NF-Y as a possible HDAC1-interacting partner. Collectively, FSH plays a dual role in keratoconus by regulating collagen accumulation through the MAP Kinase-MMP2 axis and inflammation through the HDAC1-miR-29b pathway. Human patient tears, 3D corneal hydrogel model, and co-culture model were used to identify the role of FSH in the cornea. We found that the FSH played a dual role in the regulation of corneal extracellular matrix remodeling and inflammation.
