Biology subjects

Goff, J.

Publications and source records attributed to Goff, J..

4 recordsLinked to original sources

bioRxiv2026

Ex vivo human airway epithelia modelling reveals specific alterations in lung and hematopoietic stem cell transplant recipients

Deterioration of lung function is a major cause of long-term morbidity after hematopoietic stem cell transplantation (HSCT) and lung transplantation (LT). In both settings, obliterative bronchiolitis represents the most common final pathway, with bronchiolitis obliterans syndrome (BOS), representing its clinical correlate. Understanding of the pathophysiological mechanisms leading to BOS is limited by restricted access to human lung tissue and the imperfect relevance of animal models. We hypothesize that transplantation procedures cause bronchial epithelial damage that promotes the development of BOS. To investigate this, we established ex vivo human airway epithelia (HAE) cultures from bronchial biopsies of HSCT and LT recipients, collected prior to the development of BOS, and compared them with non-transplant controls. HAE from HSCT recipients exhibited reduced tissue differentiation ability, associated with defect in mucociliary clearance and impaired barrier integrity, most markedly in one patient who subsequently developed BOS. In contrast, LT-derived HAE showed normal mucociliary clearance and barrier integrity but displayed increased mucin secretion. Donor and recipient-derived cells were detected in both paraffin-embedded biopsies and reconstructed HAE derived from transplant recipients, demonstrating epithelial chimerism. Our data highlight specific modifications of the airway epithelium after LT and HSCT that may represent a first trigger for subsequent BOS development.

Molecular Biology↗

bioRxiv2025

Reduced SK channel control of mesolimbic dopamine neuron firing drives reward seeking adaptations in chronic pain

Patients with chronic neuropathic pain typically experience affective symptoms that drive reduced quality of life and negatively impact pain management. Mesolimbic dopamine is necessary for reward valuation and learning, and the existence of a hypodopaminergic state has been proposed to underlie these affective symptoms of chronic pain. However, direct functional evidence for this hypodopaminergic state is lacking, and the mechanisms underlying its emergence over the acute to chronic pain transition are unknown. Here, we find a selective deficit in the ability of mesolimbic dopamine neurons to sustain burst firing, which is apparent uniquely at chronic timepoints following neuropathic injury. As a result, animals are unable to sustain effortful pursuit of rewards under conditions of high effort or time costs. Convergent biophysical modeling and experimental electrophysiology establish that in a spared nerve injury (SNI) model of chronic neuropathic pain, calcium-activated, small-conductance potassium (SK) channel function is impaired, resulting in lower peak firing and earlier entry into depolarization block of mesolimbic dopamine neurons. Critically, dopamine dependent reward learning, formation of cue-reward associations and locomotor activity remain intact, arguing against the interpretation of a generalized hypodopaminergic state. These results elucidate a circuit-level basis for selective motivational deficits emerging in chronic neuropathic pain.

neuroscience↗

bioRxiv2024

Extended amygdala corticotropin-releasing hormone neurons regulate sexually dimorphic changes in pair bond formation following social defeat in prairie voles (Microtus ochrogaster)

The neurobiological mechanisms underlying the connection between anxiety brought on by social stressors and the negative impact on relationship formation have remained elusive. In order to address this question, we used the social defeat model in the socially monogamous prairie vole to investigate the impact of this stress on pair bond formation. Social defeat experience inhibited partner preference formation in males but promoted preference in females. Furthermore, pair bonding increased corticotropin-releasing hormone (CRH) expression in the bed nucleus of the stria terminalis (BNST) in male prairie voles, while defeat experience increased BNST CRH expression in females. Chemogenetic excitation of BNST CRH neurons during a short cohabitation with a new partner promoted a partner preference in stress-naive prairie voles. Interestingly, chemogenetic inhibition of BNST CRH neurons during cohabitation with a new partner blocked partner preference in stress-naive males but promoted preference in defeated males. Inhibition of BNST CRH neurons also blocked partner preference in stress-naive females but did not alter preference behavior in defeated females. This study revealed sexual dimorphism in not only the impact of social defeat on pair bond formation, but also in the role BNST CRHergic neurons play in regulating changes in pair bonding following social conflict.

neuroscience↗

bioRxiv2021

Polarly localized receptor-like kinases PXC2 and IRK act redundantly during Arabidopsis root development in the radial axis

Coordination of cell division and differentiation is critical for tissue patterning during organ development. Directional signaling and cell polarity have important roles in coordination of these processes. For instance, the Arabidopsis receptor-like kinase INFLORESCENCE AND ROOT APICES KINASE (IRK) functions to restrict stele area and repress longitudinal anticlinal divisions (LADs) in the endodermis where it is polarly localized. IRK is closely related to PXY/TDR CORRELATED 2 (PXC2); here, we show that PXC2 exhibits similar polarized accumulation suggesting they have related functions. pxc2 roots have increased stele area and irk pxc2 double mutant roots show increases in stele area and endodermal LADs beyond either single mutant, indicating that polarly localized IRK and PXC2 function redundantly to repress endodermal LADs and stele area. The double mutant also exhibits agravitropic root growth and abnormal cotyledon vein patterning. Manipulation of PIN1 trafficking and (re)localization mechanisms indicate that PXC2 and/or IRK suggest a link to modulation of polar auxin transport. We conclude that IRK and PXC2 have partially redundant functions in the root, but may have independent functions that are tissue-specific. We propose that repression of endodermal LADs and stele area through a PXC2/IRK-mediated, directional signaling pathway is required for normal ground tissue cell divisions, tissue patterning, and growth in Arabidopsis roots.

plant biology↗