Airway molecular signatures in antibody-mediated lung transplant rejection

American Journal of Transplantation · 2026-02-01

Severe antibody-mediated rejection (AMR) is associated with chronic lung allograft dysfunction (CLAD) and death in lung transplant recipients. However, AMR diagnostics are imprecise, and new biomarkers are needed. We assessed whether airway inflammation gene signatures could distinguish AMR cases from controls. We analyzed small airway brush RNA sequencing from 16 AMR cases and 39 controls across 2 centers. We compared gene signatures for complement activation, molecular target of rapamycin (mTOR) signaling, and natural killer cell-mediated injury. Differential gene expression and pathway analyses sought AMR molecular features. Additionally, we evaluated the airway inflammation 2 (AI2) score, previously associated with CLAD and graft failure, in relation to AMR clinical features and survival outcomes. AMR airway brushes demonstrated transcriptional evidence of airway inflammation and upregulation of complement and natural killer cell pathways. The AI2 score was significantly elevated in AMR cases (P < .001) and was associated with AMR-compatible histology, donor-specific antibodies, complement binding, and acute graft dysfunction. Increasing AI2 scores were associated with worse retransplant-free survival, independent of other AMR features. In small airways, lung transplant AMR predominantly exhibits molecular features of cellular rejection rather than a distinct humoral rejection profile. Airway brush transcriptomics may provide a valuable tool for characterizing and prognosticating suspected AMR.

Anxiety-Associated Behaviors Following Ablation of <i>Miro1</i> from Cortical Excitatory Neurons

eNeuro · 2025-12-12

Autism spectrum disorder, schizophrenia, and bipolar disorder are neuropsychiatric conditions that manifest early in life with a wide range of phenotypes, including repetitive behavior, agitation, and anxiety ( American Psychological Association, 2013). While the etiology of these disorders is incompletely understood, recent data implicate a role for mitochondrial dysfunction ( Norkett et al., 2017; Khaliulin et al., 2025). Mitochondria translocate to intracellular compartments to support energetics and free-radical buffering; failure to achieve this localization results in cellular dysfunction ( Picard et al., 2016). Mitochondrial Rho-GTPase 1 ( Miro1 ) resides on the outer mitochondrial membrane and facilitates microtubule-mediated mitochondrial motility ( Fransson et al., 2003). The loss of MIRO1 is reported to contribute to the onset/progression of neurodegenerative diseases, including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease ( Kay et al., 2018). We have hypothesized that MIRO1 also has a role in nervous system development ( Lin-Hendel et al., 2016). To test this, we ablated Miro1 from cortical excitatory progenitors by crossing floxed Miro1 mice with Emx1-Cre mice and studied mice of both sex. We found that mitochondrial mislocalization in migrating excitatory neurons was associated with reduced brain weight, decreased cortical volume, and subtle cortical disorganization. Adult Miro1 conditional mutants exhibit agitative-like behaviors, including decreased nesting and abnormal home cage activity. The mice exhibited anxiety-like behavior and avoided confined spaces, features that have been linked to several human behavioral disorders. Our data link MIRO1 function with mitochondrial dynamics in the pathogenesis of several neuropsychiatric disorders and implicate intracellular mitochondrial dynamics to several anxiety-like behaviors.

Single-Molecule Array (Simoa) Technology as a Highly Sensitive Screening Tool for Protein–Protein Interactions

ACS Sensors · 2025-10-27 · 1 citations

Transcription factor (TF) interactions are generally considered to be weak and transient, which enables the dynamic assembly and disassembly of transcription complexes. While advantageous for modulating cellular physiology, requiring rapid adaptation, these characteristics make it challenging to identify and study TF interactions using conventional methodologies. To overcome this issue, we have adapted an ultrasensitive single-molecule array (Simoa) assay, typically used for biomarker detection, to screen for and identify TF-TF interactions. Leveraging Simoa-based digital ELISA, we have screened the human transcription factor library for interaction partners of ARX (aristaless-related homeobox), a transcription factor associated with a wide spectrum of neurodevelopmental disorders. Our successful application of Simoa technology to a high-throughput screening for protein interaction partners opens up new opportunities to study transcription factor-transcription factor interactions, especially those that have been elusive to detect.

Anxiety-associated behaviors following ablation of <i>Miro1</i> from cortical excitatory neurons

bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-22

Abstract Autism spectrum disorder, schizophrenia, and bipolar disorder are neuropsychiatric disorders that manifest early in life with a wide range of phenotypes, including repetitive behavior, agitation, and anxiety (American Psychological Association, 2013). While the etiology of these disorders is not completely understood, recent data implicate a role for mitochondrial dysfunction. To function optimally mitochondria must translocate to metabolically active intracellular compartments to support energetics and free-radical buffering; failure to achieve this localization results in cellular dysfunction (Picard et al., 2016). Mitochondrial Rho-GTPase 1 ( Miro1 ) resides on the outer mitochondrial membrane and participates in neuronal microtubule-mediated mitochondrial motility and homeostasis (Fransson et al., 2003). Previous research implicates the loss of MIRO1 as a contributor to the onset/progression of neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer’s disease, and Parkinson’s disease (Kay et al., 2018). We have hypothesized that MIRO1 also has a role in nervous system development and function (Lin-Hendel et al., 2016). To test this, we ablated Miro1 from cortical excitatory progenitors by crossing floxed Miro1 mice with Emx1-cre mice. We found that mitochondrial mis-localization in migrating excitatory neurons was associated with reduced brain weight, decreased cortical volume, and subtle disruptions in cortical organization. Adult Miro1 conditional mutants exhibit agitative-like behaviors, including decreased nesting behavior and abnormal home cage activity. Open field testing revealed anxiety-like behavior and elevated plus maze and wide/narrow box testing found the mice avoided confined spaces. Our data link MIRO1 function with mitochondrial dynamics in the pathogenesis of several neuropsychiatric disorders and implicate mitochondrial localization in anxiety-like behaviors. Significance Neuropsychological disorders such as autism spectrum disorder, schizophrenia, and bipolar disorder have overlapping symptoms and behaviors. While the mechanisms underlying these disorders are not completely understood, recent evidence suggests mitochondrial dysfunction and mis-localization within a cell could play a role. Mitochondria are organelles that provide energy and other self-regulating processes to the cell. Previous research from our lab has shown distinct dynamic localization patterns within migrating excitatory and inhibitory neurons may be important during development. To further examine the importance of mitochondrial localization, we ablated MIRO1, a protein important for coupling mitochondria to motor proteins, in excitatory neurons. Mitochondria mis-localize in migrating excitatory neurons, and this is associated with a loss of motor skills and anxiety-like behavior in post-natal mice.

Contrastive learning enhances fairness in pathology artificial intelligence systems

Cell Reports Medicine · 2025-12-01 · 4 citations

AI-enhanced pathology evaluation systems hold significant potential to improve cancer diagnosis but frequently exhibit biases against underrepresented populations due to limited diversity in training data. Here, we present the Fairness-aware Artificial Intelligence Review for Pathology (FAIR-Path), a framework that leverages contrastive learning and weakly supervised machine learning to mitigate bias in AI-based pathology evaluation. In a pan-cancer AI fairness analysis spanning 20 cancer types, we identify significant performance disparities in 29.3% of diagnostic tasks across demographic groups defined by self-reported race, gender, and age. FAIR-Path effectively mitigates 88.5% of these disparities, with external validation showing a 91.1% reduction in performance gaps across 15 independent cohorts. We find that variations in somatic mutation prevalence among populations contribute to these performance disparities. FAIR-Path represents a promising step toward addressing fairness challenges in AI-powered pathology diagnoses and provides a robust framework for mitigating bias in medical AI applications.

Congenital Malformations and Perinatal Diseases

2025-05-01

Abstract This chapter discusses perinatal congenital malformations of the brain and perinatal diseases. Congenital malformations include neurulation failure resulting in neural tube closure defects; disorders of development of the prosencephalon; malformations of the cortical plate (neuronal heterotopia, polymicrogyria, lissencephaly, and focal cortical dysplasia—a frequent cause of epilepsy in children); and disorders of hindbrain development, particularly malformations of the cerebellum. Malformations are discussed in the context of the most current understanding of neuronal migration, and the genetic basis of these disorders is provided where currently known. Destructive lesions of developing brain are described in association with a variety of situations, including both intrauterine and perinatal “hypoxia–ischemia.” These disorders may affect the neocortex, resulting in porencephaly or hydranencephaly, and the basal ganglia, resulting in malformations such as status marmoratus. Preterm infants may develop intraventricular hemorrhage or the white matter injury, with subsequent perinatal telencephalic leukoencephalopathy and periventricular leukomalacia.

Uncertainty-aware ensemble of foundation models differentiates glioblastoma from its mimics

Nature Communications · 2025-09-29 · 8 citations

Accurate pathological diagnosis is crucial in guiding personalized treatments for patients with central nervous system cancers. Distinguishing glioblastoma and primary central nervous system lymphoma is particularly challenging due to their overlapping pathology features, despite the distinct treatments required. To address this challenge, we establish the Pathology Image Characterization Tool with Uncertainty-aware Rapid Evaluations (PICTURE) system using 2141 pathology slides collected worldwide. PICTURE employs Bayesian inference, deep ensemble, and normalizing flow to account for the uncertainties in its predictions and training set labels. PICTURE accurately diagnoses glioblastoma and primary central nervous system lymphoma with an area under the receiver operating characteristic curve (AUROC) of 0.989, with the results validated in five independent cohorts (AUROC = 0.924-0.996). In addition, PICTURE identifies samples belonging to 67 types of rare central nervous system cancers that are neither gliomas nor lymphomas. Our approaches provide a generalizable framework for differentiating pathological mimics and enable rapid diagnoses for central nervous system cancer patients. Distinguishing glioblastoma and primary central nervous system lymphoma (PCNSL) remains challenging due to their overlapping pathology features. Here, the authors develop a computational tool, PICTURE, for differentiating similar pathological features enabling improved diagnosis of CNS tumours.

A fibroblast-dependent TGF-β1/sFRP2 noncanonical Wnt signaling axis promotes epithelial metaplasia in idiopathic pulmonary fibrosis

Journal of Clinical Investigation · 2024-07-09 · 66 citations

Reciprocal interactions between alveolar fibroblasts and epithelial cells are crucial for lung homeostasis, injury repair, and fibrogenesis, but underlying mechanisms remain unclear. To investigate, we administered the fibroblast-selective TGF-β1 signaling inhibitor epigallocatechin gallate (EGCG) to interstitial lung disease (ILD) patients undergoing diagnostic lung biopsy and conducted single-cell RNA-Seq on spare tissue. Biopsies from untreated patients showed higher fibroblast TGF-β1 signaling compared with nondisease donor or end-stage ILD tissues. In vivo, EGCG downregulated TGF-β1 signaling and several proinflammatory and stress pathways in biopsy samples. Notably, EGCG reduced fibroblast secreted frizzled-related protein 2 (sFRP2), an unrecognized TGF-β1 fibroblast target gene induced near type II alveolar epithelial cells (AEC2s) in situ. Using AEC2-fibroblast coculture organoids and precision-cut lung slices (PCLSs) from nondiseased donors, we found TGF-β1 signaling promotes a spread AEC2 KRT17+ basaloid state, whereupon sFRP2 then activates a mature cytokeratin 5+ (Krt5+) basal cell program. Wnt-receptor Frizzled 5 (Fzd5) expression and downstream calcineurin signaling were required for sFRP2-induced nuclear NFATc3 accumulation and KRT5 expression. These findings highlight stage-specific TGF-β1 signaling in ILD and the therapeutic potential of EGCG in reducing idiopathic pulmonary fibrosis-related (IPF-related) transcriptional changes and identify TGF-β1/noncanonical Wnt pathway crosstalk via sFRP2 as a mechanism for dysfunctional epithelial signaling in IPF/ILD.

Multicenter Assessment of the Bronchiolar Brushing Molecular Inflammation Score, AIS2, to Identify Incipient CLAD and Mortality Risk

The Journal of Heart and Lung Transplantation · 2024-04-01 · 1 citations

Malformations

2024-08-28 · 1 citations

Malformations of the central nervous system (CNS) are of major clinical importance, leading to considerable mortality and morbidity, both prenatally and postnatally. The birth prevalence of CNS malformations is between 5 and 10 per 1000 births and has been stable over the past 50 years.443,608 Data collected from Europe and the USA between 1940 and 1990 show that 8–10 per cent of stillbirths and 5–6 per cent of early neonatal deaths are the result of a CNS malformation.444 Moreover, CNS malformations are present in around 15 per cent of infants dying from causes associated with birth defects.945