Biology subjects

Thomas, M. J.

Publications and source records attributed to Thomas, M. J..

At least 19 recordsLinked to original sources

bioRxiv2026

The basolateral amygdala dopamine system shapes dynamic drug seeking states

Drug-associated sensory cues and contexts exert powerful influence over drug seeking motivation, but in vivo brain mechanisms governing this process remain unclear. Here, we recorded and manipulated dopamine signaling and dopamine receptor D1+ neuronal activity in the basolateral amygdala (BLA) to investigate their contributions to dynamic sensory-guided cocaine seeking in rats. First, we show that cocaine exposure sensitizes dopamine transmission from ventral tegmental area dopamine neurons projecting to the BLA. We then employed an intermittent access cocaine self-administration paradigm that prompted robust binge-like cocaine seeking that was heavily guided by shifts in the sensory environment. Cued transitions to drug available states evoked large and sustained BLA dopamine signals and transient neuronal responses from BLA D1+ neurons. BLA dopamine signals and D1-neuron activity came to preferentially encode these drug availability states, which hierarchically modulated neural activity during drug seeking actions and predicted different aspects of behavior. Finally, we found that optogenetically enhancing BLA D1-neuron activity at drug availability state transitions potentiated cocaine binging. Our findings provide new insight into the neural control of addiction-related behavior, identifying the dopaminergic amygdala as a key interface between the environment and decisions to engage in vigorous drug use.

neuroscience↗

bioRxiv2026

Experience-Dependent Gain Modulation Drives Thermosensory Responses in Behavior

Sensory neurons must extract behaviorally relevant features from dynamic environments while maintaining sensitivity across wide stimulus ranges. To understand how sensory encoding adapts to experience during behavior, we combine long-duration calcium imaging in freely moving C. elegans with a temperature-trajectory playback paradigm to determine how the thermosensory neuron AFD extracts behaviorally relevant sensory features during navigation. We observe that AFD functions as a leaky integrator of recently experienced temperature changes, accumulating thermal inputs over a rolling window of tens of seconds, resulting in calcium levels that represent recent temperature dynamics during runs. Importantly, we determine that AFD selectively amplifies responses to temperature changes near its learned preferred temperature. This experience-dependent gain control aligns encoding with the navigational goal, providing a mechanism for representing temperature preference within a derivative-based sensory system. A minimal mathematical model incorporating derivative detection, leaky integration, and temperature-dependent gain captures the calcium dynamics over a range of stimuli, and a simulation based on the mathematical model predicts goal-oriented locomotor strategies across stimulus regimes. Together, these findings show how gain control allows a derivative-based sensory code to represent an absolute goal and guide locomotory strategies during navigation. HighlightsO_LIAFD encodes recent temperature changes over behaviorally relevant timescales. C_LIO_LIAFD amplifies temperature-change responses within a learned temperature-centered gain window. C_LIO_LIGain control provides a mechanism for representing distance to temperature preference within the derivative-based sensory system. C_LIO_LIA mathematical model and simulation of derivative sensing, leaky integration, and gain control predicts AFD calcium responses and goal-oriented locomotory strategies across stimulus regimes. C_LI

neuroscience↗

bioRxiv2026

Glycolytic Specialization Shapes Neuronal Physiology and Function in vivo

Neurons perform diverse functions that impose distinct energetic demands, but how energy-metabolic pathways are matched to these functions in vivo remains unknown. Here we show that two functionally divergent sister chemosensory neurons in C. elegans, ASEL and ASER, exhibit asymmetric glycolytic flux, with ASER exhibiting high and ASEL having low levels of glycolysis. Metabolic imaging, metabolic network modeling, and electrophysiology measurements reveal that ASERs elevated glycolysis supports a hyperpolarized resting potential, low input resistance, and rapid repolarization that enable a distinct functional role compared to ASEL. Impairing glycolysis collapses these electrophysiological specializations without abolishing neuronal excitability, and selectively disrupts ASERs calcium responses while leaving ASEL largely unaffected. These findings demonstrate that neuron-specific glycolytic programs shape core biophysical properties and are required for functional identity in vivo, establishing metabolism as an active determinant of neuronal physiology.

neuroscience↗

bioRxiv2025

Cocaine sensitization and accumbens shell plasticity depend on biological sex and gonadal hormones in C57BL/6J mice

Biological sex as a defining variable in drug sensitivity remains poorly understood. Here, we combine behavioral and electrophysiological analyses to examine the influence of sex and gonadal hormones on cocaine-induced psychomotor sensitization and nucleus accumbens shell (NAcSh) plasticity in the prominent C57BL/6J mouse strain. Males exhibited greater cocaine-evoked locomotor activity than females; castration attenuated responses, whereas ovariectomy enhanced them. This behavioral phenotype is opposite to what occurs in rats. A 10-14 day abstinence period abolished the sex difference in intact animals, and gonadectomy reduced cocaine-induced behavioral plasticity. Recordings from 309 medium spiny neurons revealed sex-dependent NAcSh plasticity. In males, cocaine decreased neuronal excitability, while in females it induced estrous cycle-dependent plasticity characterized by reduced excitability during diestrus relative to estrus. These effects were driven by cocaine-induced modulation of voltage-gated sodium channels. Cocaine potentiated glutamatergic strength in males but elicited estrous cycle-dependent depotentiation in females. These adaptations in excitability and glutamatergic strength were abolished by gonadectomy, and paralleled diminished behavioral plasticity during abstinence. These data illustrate that biological sex and hormonal milieu critically shape cocaine-induced plasticity, offering a more nuanced framework than the traditional notion of heightened female sensitivity to drugs of abuse.

neuroscience↗

bioRxiv2025

Basolateral amygdala dopamine transmits a nonassociative emotional salience signal

Adaptive decision making relies on proper disambiguation of upcoming positive and negative events. The basolateral amygdala (BLA) is central to this, assigning emotional value to stimuli to facilitate appropriate behavior. The ventral tegmental area (VTA), which is classically known to regulate associative learning and incentive motivation via dopamine projections to the striatum, also contains strong dopamine projections to the BLA, but this system has received much less attention. Here, we investigated how in vivo BLA dopamine signaling is engaged during valenced experiences in associative learning. First, we show that BLA dopamine signals scale with intensity of aversive stimuli, but not reward value, and reward-predictive cues evoke BLA dopamine signals that diminish, rather than grow, with training. As the complexity of the learning context was increased, where rats actively differentiated between various cue types signaling threat, reward, safety, and neutral associations, the magnitude of cue-evoked BLA dopamine re-scaled to report the level of relative emotional saliency. Fear and safety cues prompted larger, more sustained dopamine signals compared to reward and neutral cues. Despite these distinctions, cue-evoked dopamine signals did not reliably correlate with behavioral expression, and optogenetically enhancing BLA dopamine did not alter freezing behavior. Together, these results indicate that dopamine signaling in the BLA encodes the emotional weight of sensory transitions, but not the associative strength or value of conditioned cues. Our findings broaden the theoretical landscape of dopamine heterogeneity, showing that BLA dopamine contributes to tagging affective states, in support of dynamic discernment of relative stimulus importance during learning.

neuroscience↗

bioRxiv2025

AXL-GAS6/PROS1 Interaction: A Critical Switch Between Aberrant- and Healthy Repair Following Alveolar Lung Injury

RationaleIdiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by aberrant alveolar repair and excessive fibrosis. The TAM-family receptor tyrosine kinase AXL, activated by GAS6 and PROS1, is implicated in tissue remodeling, but ligand-specific AXL signaling during alveolar repair remains poorly defined. ObjectivesTo investigate ligand specific AXL signaling in IPF and how it impacts epithelial proliferation and repair after alveolar injury in-vivo and in-vitro. MethodsSingle cell RNA sequencing was utilized to understand cell specific expression patterns in IPF patients, followed by functional studies in primary human cell culture and functional spatial digital profiling (FuncOmap) analysis in patient tissue. Longitudinal assessment of repair process after alveolar-specific injury in-vivo was used to complement the in-vitro approach. ResultsAXL expression showed enrichment in basal and aberrant basaloid cells of IPF patients. In-vitro GAS6 increased proliferation of basal cells, while PROS1 counteracted this effect. FuncOmap analysis demonstrates direct in-situ interactions between AXL and both ligands, providing evidence for biological relevance. Investigating longitudinal repair processes in-vivo revealed dynamic regulation of AXL ligands as well as AXL. ConclusionsThese findings highlight the importance of ligand-specific AXL signaling in lung repair and suggest that it dysregulation may contribute to IPF pathogenesis, offering potential therapeutic targets for restoring normal repair processes.

molecular biology↗

bioRxiv2025

Contrasting responses of control and fibrotic lung fibroblasts to fibrotic stimuli: the role of osteoprotegerin in extracellular matrix remodeling

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by dysregulated wound healing, leading to excessive production of extracellular matrix (ECM) proteins, particularly collagen, by activated fibroblasts. Osteoprotegerin (OPG), a soluble protein associated with ECM remodeling in bone, has been found in higher levels in serum and lung tissue of IPF patients compared to controls. However, whether OPG is associated with ECM remodeling by fibroblasts in lung fibrosis remains poorly understood. In this study we assessed differences in OPG levels in ECM-derived hydrogels from non-disease controls and patients with IPF encapsulated with primary human lung fibroblasts from control and patients with IPF (7 days). OPG levels were assessed in a collected culture medium and stained lung tissue sections, and related to biomechanical properties. Fibrotic human lung fibroblasts secreted and deposited more OPG compared to controls, which was observed in both non-diseased and IPF ECM hydrogels. OPG levels correlated significantly with matrix stiffness and collagen fiber structural properties, but only in IPF hydrogels, independent of fibroblast source. Strikingly, we also observed opposite correlations for control and fibrotic fibroblasts in fibrotic hydrogels. Control fibroblasts within a fibrotic microenvironment, secreted less OPG when hydrogel stiffness increased and deposited more OPG when collagen fibers were more aligned. Interestingly, fibrotic fibroblasts secreted more OPG when collagen fiber length increased and when collagen fiber curvature increased. Overall, our findings suggest that control and fibrotic lung fibroblasts exhibited opposite behavior with respect to OPG and ECM remodeling under fibrotic conditions and this may have consequences for matrix stiffness

cell biology↗

bioRxiv2024

PTX3 Governs Fibroblast-Epithelial Dynamics in Lung Injury and Repair

Dysfunctional interactions between fibroblasts and epithelial cells contribute to the progression of chronic lung diseases, including idiopathic pulmonary fibrosis (IPF). In this study, we utilized a coculture model of human small airway epithelial cells and fibroblasts to investigate intercellular communication during disease progression. Our transcriptomic and proteomic profiling reveal that fibroblasts repair epithelial cells in acute injury by boosting epithelial fatty acid metabolism; conversely, they exacerbate epithelial damage in chronic injury scenarios. By delineating regulators involved in these responses, we identified pentraxin 3 (PTX3) as a key antifibrotic factor secreted by fibroblasts in response to acute epithelial injury. Importantly, PTX3 levels are decreased in bronchoalveolar lavage (BAL) samples from IPF patients compared to non-fibrotic controls, indicating a potential link between diminished PTX3 levels and fibrosis progression. Furthermore, adding PTX3 to chronically injured epithelial-fibroblast cocultures mitigated the pro-fibrotic response and restored the epithelial barrier integrity. These findings highlight the dual roles of fibroblasts and the critical function of PTX3 in lung injury and repair, offering insights for therapeutic strategies.

molecular biology↗

bioRxiv2024

JUNB O-GlcNAcylation-mediated promoter accessibility of metabolic genes modulates distinct epithelial lineage in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a lethal disease with substantial unmet medical needs. While aberrant epithelial remodelling is a key factor in IPF progression, the molecular mechanisms behind this process remain elusive. Using a patient-derived 3D distal airway epithelial organoid model, we successfully recapitulate important IPF features, including the emergence of aberrant KRT5+/COL1A1+ basal cells and a metabolic shift towards increased O-linked {beta}-N-acetylglucosamine (O-GlcNAc) levels. Consistent with this, single-cell analysis of accessible chromatin reveals an increased chromatin accessibility in these aberrant basal cells, particularly at JUNB motif-enriched promoter regions of metabolic genes. O-GlcNAcylation shapes JUNB function and promotes a pro-fibrotic response to chronic injury, leading to aberrant epithelial remodelling. Site-specific deletion of O-GlcNAcylation on JUNB attenuates the metaplastic differentiation of basal cells, thereby aiding in the restoration of the alveolar lineage. Together, these data establish a novel link between metabolic dysregulation, mediated by the O-GlcNAc-JUNB axis, and bronchiolization in IPF, offering new therapeutic strategies to treat this fatal disease.

cell biology↗

bioRxiv2023

Spatial Transcriptomic Characterization of Novel Pathologic Niches in IPF

An unmet medical need persists in Idiopathic Pulmonary fibrosis (IPF), for which treatments additional to anti-fibrotic therapy are needed. Single cell RNA sequencing (scRNA-seq) has advanced our understanding of IPF with cell type-specific insights but lacks cellular tissue context. Spatial transcriptomics addresses this by providing spatially resolved gene expression, enabling gene and cell type localization within the tissue environment. We profiled IPF and control patient lung tissue sections using spatial transcriptomics and combined the data with an atlas of integrated IPF scRNA-seq datasets. Through computational analysis, we identified three disease-associated pathologic niches with unique cellular composition / localization and analyzed their cell-cell communication. We identified the Fibrotic niche, comprising Myofibroblasts and Aberrant Basaloid cells, preferentially located around airways and close to the Airway Macrophage niche in the lumen, containing SPP1+ Macrophages. We also identified the Immune niche, distinct foci of lymphoid cells in fibrotic tissue, surrounded by remodeled endothelial vessels. TEASERSpatial transcriptomics localizes genes and cell types in the tissue and identifies pathological cellular niches in IPF and control lungs.

systems biology↗

bioRxiv2023

Scavenger receptor class B type I is required for efficient glucose uptake and metabolic homeostasis in adipocytes

Obesity is a worldwide epidemic and places individuals at a higher risk for developing comorbidities that include cardiovascular disease and type 2 diabetes. Adipose tissue contains adipocytes that are responsible for lipid metabolism and reducing misdirected lipid storage. Adipocytes facilitate this process through insulin-mediated uptake of glucose and its subsequent metabolism into triglycerides for storage. During obesity, adipocytes become insulin resistant and have a reduced ability to mediate glucose import, thus resulting in whole-body metabolic dysfunction. Scavenger receptor class B type I (SR-BI) has been implicated in glucose uptake in skeletal muscle and adipocytes via its native ligands, apolipoprotein A-1 and high-density lipoproteins. Further, SR-BI translocation to the cell surface in adipocytes is sensitive to insulin stimulation. Using adipocytes differentiated from ear mesenchymal stem cells isolated from wild-type and SR-BI knockout (SR-BI-/-) mice as our model system, we tested the hypothesis that SR-BI is required for insulin-mediated glucose uptake and regulation of energy balance in adipocytes. We demonstrated that loss of SR-BI in adipocytes resulted in inefficient glucose uptake regardless of cell surface expression levels of glucose transporter 4 compared to WT adipocytes. We also observed reduced glycolytic capacity, increased lipid biosynthesis, and dysregulated expression of lipid metabolism genes in SR-BI-/- adipocytes compared to WT adipocytes. These results partially support our hypothesis and suggest a novel role for SR-BI in glucose uptake and metabolic homeostasis in adipocytes.

biochemistry↗

bioRxiv2023

Three dimensional fibrotic extracellular matrix directs microenvironment fiber remodeling by fibroblasts

Idiopathic pulmonary fibrosis (IPF), for which effective treatments are limited, results in excessive and disorganized deposition of an aberrant extracellular matrix (ECM). An altered ECM microenvironment is postulated to contribute to disease perpetuation in a feed-forward manner through inducing profibrotic behavior by lung fibroblasts, the main producers and regulators of ECM. Here, we examined this hypothesis in a 3D in vitro model system by growing primary human lung fibroblasts in ECM-derived hydrogels from non-fibrotic (control) or IPF lung tissue. Culture of fibroblasts in fibrotic hydrogels did not trigger a change in the overall amount of collagen or glycosaminoglycans but did cause a drastic change in fiber organization compared to culture in control hydrogels. Mechanical properties of fibrotic hydrogels were modified by fibroblasts while control hydrogels were not. These results illustrate how the 3D microenvironment plays a crucial role in directing cells to exhibit pro-fibrotic responses by providing biochemical and/or biomechanical cues.

pathology↗

bioRxiv2023

Fundamental Sex Differences in Cocaine-Induced Plasticity of D1- and D2-MSNs in the Mouse Nucleus Accumbens Shell

Cocaine-induced plasticity in the nucleus accumbens shell of males occurs primarily in D1 dopamine receptor expressing neurons (D1-MSNs), with little if any impact on D2 dopamine receptor neurons (D2-MSNs). Using ex vivo whole cell recordings in male and female mice, we observe alterations in D1-MSN excitability across the estrous cycle similar in magnitude to the actions of cocaine in males. Furthermore, cocaine shifts estrous cycle-dependent plasticity from intrinsic excitability changes in D1-MSNs to D2-MSNs. Overall, while there are similar cocaine-induced disparities regarding the relative excitability of D1-MSN versus D2-MSN between the sexes, in males this is mediated through reduced D1-MSN excitability, whereas in females it is due to heightened D2-MSN excitability.

neuroscience↗

bioRxiv2023

Physiological acetic acid concentrations from ethanol metabolism stimulate accumbens shell neurons via NMDAR activation in a sex-dependent manner

Recent studies have implicated the ethanol metabolite, acetic acid, as neuroactive, perhaps even more so than ethanol itself. In this study, we investigated sex-specific metabolism of ethanol (1, 2, and 4g/kg) to acetic acid in vivo to guide electrophysiology experiments in the accumbens shell (NAcSh), a key node in the mammalian reward circuit. There was a sex-dependent difference in serum acetate production, quantified via ion chromatography only at the lowest dose of ethanol (males>females). Ex vivo electrophysiology recordings of NAcSh neurons in brain slices demonstrated that physiological concentrations of acetic acid (2 mM and 4 mM) increased NAcSh neuronal excitability in both sexes. N-methyl-D-aspartate receptor (NMDAR) antagonists, AP5, and memantine robustly attenuated the acetic acid-induced increase in excitability. Acetic acid-induced NMDAR-dependent inward currents were greater in females compared to males. These findings suggest a novel NMDAR-dependent mechanism by which the ethanol metabolite, acetic acid, may influence neurophysiological effects in a key reward circuit in the brain.

neuroscience↗

bioRxiv2021

Intraspecific variation in migration timing of green sturgeon in the Sacramento River system

BackgroundUnderstanding movement patterns of anadromous fishes is critical to conservation management of declining wild populations and preservation of habitats. Yet, infrequent observations of individual animals fundamentally constrain accurate descriptions of movement dynamics. MethodsIn this study, we synthesized over a decade (2006-2018) of acoustic telemetry tracking observations of green sturgeon (Acipenser medirostris) in the Sacramento River system to describe major anadromous movement patterns. ResultsWe observed that green sturgeon exhibited a unimodal in-migration during the spring months but had a bimodal distribution of out-migration timing, split between an early out-migration (32%) group during May - June, or alternatively, holding in the river until a late out-migration (68%), November - January. Focusing on these out-migration groups, we found that river discharge, but not water temperature, may cue the timing of migration, and that fish showed a tendency to maintain out-migration timing between subsequent spawning migration events. ConclusionsWe recommend that life history descriptions of green sturgeon in this region reflect the distinct out-migration periods described here. Furthermore, we encourage the continued use of biotelemetry to describe migration timing and life history variation, not only this population but other green sturgeon populations and other species.

ecology↗

bioRxiv2021

Transcranial Ultrasound Stimulation in Anterior Cingulate Cortex Impairs Information Sampling and Learning in Loss Contexts

Neuronal subgroups in anterior cingulate cortex (ACC) and the anterior striatum (STR) encode the reward structure of a given environment. But whether or how this reward information is used to guide information sampling, optimize decision making, or motivate behavior in cognitively challenging situations has remained elusive. Here, we causally tested these scenarios by transiently disrupting ACC and STR of rhesus monkeys with transcranial ultrasound with a learning task that independently varied cognitive and motivational demands. We found that disrupting the ACC, but not the STR, prolonged information sampling and reduced learning efficiency whenever the motivational payoff was low. These impairments were most pronounced at high cognitive demands and based on an inability to use loss experiences to improve performance. These results provide causal evidence that the ACC is necessary for motivation, to overcome anticipated costs from negative (loss) outcomes, and for cognition, to enhance visual information sampling during adaptive behavior. HIGHLIGHTSO_LITranscranial ultrasound stimulation of the anterior cingulate cortex disrupts learning after loss experience. C_LIO_LIThe ultrasound-induced learning deficit is exacerbated at high cognitive load. C_LIO_LIThe ultrasound-induced learning deficit is accompanied by inefficient fixational information sampling. C_LIO_LIAnterior cingulate cortex causally supports credit assignment of aversive outcomes to visual features. C_LI

neuroscience↗

bioRxiv2021

Kinetic characterization and thermostability of C. elegans cytoplasmic and mitochondrial malate dehydrogenases

Malate dehydrogenase (MDH) catalyzes the conversion of NAD+ and malate to NADH and oxaloacetate in the last step of the citric acid cycle. Eukaryotes have at least two MDH isozymes, one that is imported into the mitochondria and one that remains in the cytoplasm. We overexpressed and purified Caenorhabditis elegans cytoplasmic MDH-1 (F46E10.10) and mitochondrial MDH-2 (F20H11.3) in E. coli. Our goal was to compare the kinetic and structural properties of these enzymes because C. elegans can survive adverse environmental conditions, such as lack of food and elevated temperatures. In steady-state enzyme kinetics assays, we determined that the KM values for oxaloacetate were 54 and 52 M, and the KM values for NADH were 61 and 107 M, for MDH-1 and MDH-2, respectively. We partially purified endogenous MDH from a mixed population of worms and separated MDH-1 from MDH-2 using anion exchange chromatography. Both endogenous enzymes had a KM for oxaloacetate similar to that of the corresponding recombinant enzyme. The reaction velocities of the recombinant enzymes had slightly different temperature-dependencies: MDH-1 and MDH-2 had maximum activity at 40 {degrees}C and 35 {degrees}C, respectively. In a thermotolerance assay, MDH-1 was much more thermostable than MDH-2. Molecular homology modeling predicted that MDH-1 had more salt-bridges between the subunits than mammalian MDH1 enzymes, and these ionic interactions may contribute to its thermostability. In contrast, the MDH-2 homology model predicted fewer ionic interaction between the subunits compared to mammalian MDH2 enzymes. These results suggest that the increased structural stability of MDH-1 may facilitate its ability to remain active in adverse environmental conditions. In contrast, MDH-2 may use other strategies, such as protein binding partners, to function under similar conditions.

biochemistry↗

bioRxiv2021

Characterization of a flexible AAV-DTR/DT mouse model of acute epithelial lung injury

Background & aimRecurring epithelial injury and aberrant repair are considered as a major driver of idiopathic pulmonary fibrosis (IPF) leading to chronic inflammation, fibroblast activation and ultimately to scarring and stiffening of the lung. As decline of lung function is the first reported symptom by IPF patients and occurs once fibrosis is firmly established, animal models are required to study early disease-driving mechanisms. MethodsWe developed a novel and flexible mouse model of acute epithelial injury based on adeno-associated virus (AAV) variant 6.2 mediated expression of the human diphtheria toxin receptor (DTR). Following intratracheal administration of diphtheria toxin (DT), a cell-specific death of bronchial epithelial and alveolar epithelial type II cells can be observed. ResultsDetailed characterization of the AAV-DTR/DT mouse model revealed increasing cell numbers in bronchoalveolar lavage (BAL; macrophages, neutrophils, and atypical cells) and elevation of apoptotic cells and infiltrated leukocytes in lung tissue, which were dependent of viral genome load and DT dose. Cytokine levels in BAL fluid showed different patterns dependent of viral genome load with IFN{gamma}, TNF, and IP-10 increasing and IL-5 and IL-6 decreasing, while lung function was not affected. Additionally, laser-capture microdissection-based proteomics of bronchial and alveolar epithelium showed upregulated immune and inflammatory response in all epithelial cell regions and extracellular matrix deposition in infiltrated alveoli, while proteins involved in pulmonary surfactant synthesis, alveolar fluid clearance and alveolar-capillary barrier were downregulated in the parenchyma. ConclusionOur novel AAV-DTR/DT model resembles specific aspects of pulmonary diseases like IPF and acute respiratory distress syndrome. Short summary for social mediaA novel and flexible mouse model of acute epithelial lung injury based on AAV-mediated expression of the human diphtheria toxin receptor followed by intratracheal instillation of diphtheria toxin resembles specific aspects of pulmonary diseases like IPF.

cell biology↗