Biology subjects

Patel, P.

Publications and source records attributed to Patel, P..

At least 91 records · Page 5Linked to original sources

bioRxiv2020

Reproductive phasiRNA loci and DICER-LIKE5, but not microRNA loci, diversified in monocotyledonous plants

In monocots other than maize and rice, the repertoire and diversity of microRNAs (miRNAs) and the populations of phased, secondary, small interfering RNAs (phasiRNAs) are poorly characterized. To remedy this, we sequenced small RNAs from vegetative and dissected inflorescence tissue in 28 phylogenetically diverse monocots and from several early-diverging angiosperm lineages, as well as publicly available data from 10 additional monocot species. We annotated miRNAs, siRNAs and phasiRNAs across the monocot phylogeny, identifying miRNAs apparently lost or gained in the grasses relative to other monocot families, as well as a number of tRNA fragments misannotated as miRNAs. Using our miRNA database cleaned of these misannotations, we identified conservation at the 8th, 9th, 19th and 3 end positions that we hypothesize are signatures of selection for processing, targeting, or Argonaute sorting. We show that 21-nt reproductive phasiRNAs are far more numerous in grass genomes than other monocots. Based on sequenced monocot genomes and transcriptomes, DICER-LIKE5 (DCL5), important to 24-nt phasiRNA biogenesis, likely originated via gene duplication before the diversification of the grasses. This curated database of phylogenetically diverse monocot miRNAs, siRNAs, and phasiRNAs represents a large collection of data that should facilitate continued exploration of small RNA diversification in flowering plants.

plant biology↗

bioRxiv2020

Mechanosensitive activation of mTORC1 mediates ventilator induced lung injury during the acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a highly lethal condition that impairs lung function and causes respiratory failure. Mechanical ventilation maintains gas exchange in patients with ARDS, but exposes lung cells to physical forces that exacerbate lung injury. Our data demonstrate that mTOR complex 1 (mTORC1) is a mechanosensor in lung epithelial cells and that activation of this pathway during mechanical ventilation exacerbates lung injury. We found that mTORC1 is activated in lung epithelial cells following volutrauma and atelectrauma in mice and humanized in vitro models of the lung microenvironment. mTORC1 is also activated in lung tissue of mechanically ventilated patients with ARDS. Deletion of Tsc2, a negative regulator of mTORC1, in epithelial cells exacerbates physiologic lung dysfunction during mechanical ventilation. Conversely, treatment with rapamycin at the time mechanical ventilation is initiated prevents physiologic lung injury (i.e. decreased compliance) without altering lung inflammation or barrier permeability. mTORC1 inhibition mitigates physiologic lung injury by preventing surfactant dysfunction during mechanical ventilation. Our data demonstrate that in contrast to canonical mTORC1 activation under favorable growth conditions, activation of mTORC1 during mechanical ventilation exacerbates lung injury and inhibition of this pathway may be a novel therapeutic target to mitigate ventilator induced lung injury during ARDS.

molecular biology↗

bioRxiv2019

Controlling a robotic arm for functional tasks using a wireless head-joystick: A case study of a child with congenital absence of upper and lower limbs

Children with movement impairments needing assistive devices for activities of daily living often require novel methods for controlling these devices. Body-machine interfaces, which rely on body movements, are particularly well-suited for children as they are non-invasive and have high signal-to-noise ratios. Here, we examined the use of a head-joystick to enable a child with congenital absence of all four limbs to control a seven degree-of-freedom robotic arm. Head movements were measured with a wireless inertial measurement unit and used to control a robotic arm to perform two functional tasks - a drinking task and a block stacking task. The child practiced these tasks over multiple sessions; a control participant performed the same tasks with a manual joystick. Our results showed that the child was able to successfully perform both tasks, with movement times decreasing by ~40-50% over 6-8 sessions of training. The childs performance with the head-joystick was also comparable to the control participant using a manual joystick. These results demonstrate the potential of using head movements for the control of high degree-of-freedom tasks in children with limited movement repertoire.

neuroscience↗

bioRxiv2019

PharmOmics: A Species- and Tissue-specific Drug Signature Database and Online Tool for Toxicity Prediction and Drug Repurposing

Drug development has been hampered by a high failure rate in clinical trials due to efficacy or safety issues not predicted by preclinical studies in model systems. A key contributor is our incomplete understanding of drug functions across organ systems and species. Therefore, elucidating species- and tissue-specific actions of drugs can provide systems level insights into therapeutic efficacy, potential adverse effects, and interspecies differences that are necessary for more effective translational medicine. Here, we present a comprehensive drug knowledgebase and analytical tool, PharmOmics, comprised of genomic footprints of drugs in individual tissues from human, mouse, and rat transcriptome data from GEO, ArrayExpress, TG-GATEs, and DrugMatrix. Using multi-species and multi-tissue gene expression signatures as molecular indicators of drug functions, we developed gene network-based approaches for drug repositioning. We demonstrate the potential of PharmOmics to predict drugs for new disease indications and validated two predicted drugs for non-alcoholic fatty liver disease in mice. We also examined the potential of PharmOmics to identify drugs related to hepatoxicity and nephrotoxicity. By combining tissue- and species-specific in vivo drug signatures with biological networks, PharmOmics serves as a complementary tool to support drug characterization.

systems biology↗

bioRxiv2019

Nanoparticle delivery of microRNA-146a regulates mechanotransduction in lung macrophages and mitigates lung injury during mechanical ventilation

During mechanical ventilation, injurious biophysical forces exacerbate lung injury. These forces disrupt alveolar capillary barrier integrity, trigger proinflammatory mediator release, and differentially regulate genes and non-coding oligonucleotides such as microRNAs. In this study, we identify miR-146a as a mechanosensitive microRNA in alveolar macrophages that has therapeutic potential to mitigate lung injury during mechanical ventilation. We used humanized in-vitro systems, mouse models, and biospecimens from mechanically ventilated patients to elucidate the expression dynamics of miR-146a that might be required to decrease lung injury during mechanical ventilation. We found that the endogenous increase in miR-146a following injurious was relatively modest and not sufficient to prevent lung injury. However, when miR-146a was highly overexpressed using a nanoparticle-based delivery platform in vivo, it was sufficient to prevent lung injury. These data indicate that the endogenous increase in microRNA-146a during MV is a compensatory response that only partially limits VILI and that nanoparticle delivery approaches that significantly over-express microRNA-146a in AMs is an effective strategy for mitigating VILI.

molecular biology↗

bioRxiv2019

DAF-16 and SMK-1 contribute to innate immunity during adulthood in Caenorhabditis elegans

Aging is accompanied by a progressive decline in immune function termed \"immunosenescence\". Deficient surveillance coupled with the impaired function of immune cells compromises host defense in older animals. The dynamic activity of regulatory modules that control immunity appears to underlie age-dependent modifications to the immune system. In the roundworm Caenorhabditis elegans levels of the PMK-1 p38 MAP kinase diminish over time, reducing the expression of immune effectors that clear bacterial pathogens. Along with the PMK-1 pathway, innate immunity in C. elegans is regulated by the insulin signaling pathway. Here we asked whether DAF-16, a Forkhead box (FOXO) transcription factor whose activity is inhibited by insulin signaling, plays a role in host defense later in life. While in younger worms DAF-16 remains in an inactive state unless stimulated by environmental insults, we found that even in the absence of acute stress the transcriptional activity of DAF-16 increases in an age-dependent manner. Beginning in the reproductive phase of adulthood, DAF-16 upregulates a subset of its transcriptional targets, including genes required to kill ingested microbes. Accordingly, DAF-16 has little to no role in larval immunity, but functions specifically during adulthood to confer resistance to bacterial pathogens. We found that DAF-16-mediated immunity in adults requires SMK-1, a regulatory subunit of the PP4 protein phosphatase complex. Our data suggest that as the function of one branch of the innate immune system of C. elegans (PMK-1) declines over time, DAF-16-mediated immunity ramps up to become the predominant means of protecting adults from infection, thus reconfiguring immunity later in life.

immunology↗

bioRxiv2019

Input dose differentiation by NF-κB

Cells receive a wide range of dynamic signaling inputs during immune regulation, but how gene regulatory networks measure and interpret such dynamic inputs is not understood. Here, we used microfluidic live-cell analysis and mathematical modeling to study how NF-{kappa}B pathway in single-cells responds to time-varying immune inputs such as increasing, decreasing or fluctuating cytokine signals. Surprisingly, we found that NF-{kappa}B acts as a differentiator, responding strictly to the absolute difference in cytokine concentration, and not to the concentration itself. Our analyses revealed that negative feedbacks by the regulatory proteins A20 and I{kappa}B enable dose differentiation by providing short-term memory of prior cytokine level and continuously resetting kinase cycling and receptor levels. Investigation of NF-{kappa}B target gene expression showed that cells create unique transcriptional responses under different dynamic cytokine profiles. Our results demonstrate how cells use simple network motifs and transcription factor dynamics to efficiently extract information from complex signaling environments.

systems biology↗

bioRxiv2019

Cortical encoding of melodic expectations in human temporal cortex

Humans engagement in music rests on underlying elements such as the listeners cultural background and general interest in music, all shaping the way music is processed in the brain and perceived. Crucially, these factors modulate how listeners anticipate musical events, a process inducing instantaneous neural responses as the music confronts these expectations. Measuring such neural correlates would represent a direct window into high-level brain processing of music. Here we recorded electroencephalographic and electrocorticographic brain responses as participants listened to Bach melodies. We assessed the relative contributions of the acoustic versus melodic components of the music to the neural signal. Acoustic features included envelope and its derivative. Melodic features included information on melodic progressions (pitch) and their tempo (onsets), which were extracted from a Markov model predicting the next note based on a corpus of Western music and the preceding proximal musical context. We related the music to brain activity with a linear temporal response function, and demonstrated that cortical responses to music encode melodic expectations. Specifically, individual-subject neural signals were better predicted by a combination of acoustic and melodic expectation features than by either alone. This effect was most pronounced at response latencies up to 350ms, and in both planum temporale and Heschls gyrus. Finally, expectations of pitch and onset-time of musical notes exerted independent cortical effects, and such influences were modulated by the listeners musical expertise. Overall, this study demonstrates how the interplay of experimental and theoretical approaches can yield novel insights into the cortical encoding of melodic expectations.

neuroscience↗

bioRxiv2019

Deep learning reveals hidden variables underlying NF-κB activation in single cells

Individual cells show great heterogeneity when responding to environmental cues. For example, under cytokine stimulation some cells activate immune signaling pathways while others completely ignore the signal. The underlying sources of cellular variability have been inaccessible due to the destructive nature of experiments. Here we apply deep learning, live-cell analysis, and mechanistic modeling to uncover hidden variables controlling NF-{kappa}B activation in single-cells. Our computer-vision algorithm accurately predicts cells that will respond to pro-inflammatory TNF stimulation and shows that single-cell activation is pre-determined by minute amounts of \"leaky\" nuclear NF-{kappa}B localization before stimulation. Theoretical analysis predicts and experiments confirm that the ratio of NF-{kappa}B to its inhibitor I{kappa}B determines the activation probability of a given cell. Our results demonstrate how computer vision can study living-cells without the use of destructive measurements and settles the question of whether heterogenous NF-{kappa}B activation is controlled by pre-existing deterministic variables or purely stochastic ones.

systems biology↗

bioRxiv2019

The Moorfields AMD Database Report 2 - Fellow Eye Involvement with Neovascular Age-related Macular Degeneration

Background/AimsNeovascular age-related macular degeneration (nAMD) is frequently bilateral, and previous reports on fellow eyes have assumed sequential treatment after a period of treatment of the first eye only. The aim of our study was to analyse baseline characteristics and visual acuity (VA) outcomes of fellow eye involvement with nAMD, specifically differentiating between sequential and non-sequential (due to macular scarring in the first eye) anti-vascular endothelial growth factor treatment and timelines for fellow eye involvement.\n\nMethodsRetrospective, electronic medical record database study of the Moorfields AMD database of 8174 eyes/120,756 single entries with data extracted between October 21, 2008 and August 9, 2018. The dataset for analysis consisted of 1180 sequential, 413 nonsequential, and 1110 unilateral eyes.\n\nResultsMean VA of sequentially treated fellow eyes at baseline was significantly higher (62{+/-}13), VA gain over two years lower (0.65{+/-}14), and proportion of eyes with good VA ([≥]20/40 or 70 letters) higher (46%) than the respective first eyes (baseline VA 54{+/-}16, VA gain at two years 5.6{+/-}15, percentage of eyes with good VA 38%). Non-sequential fellow eyes showed baseline characteristics and VA outcomes similar to first eyes. Fellow eye involvement rate was 32% at two years, and median time interval to fellow eye involvement was 71 (IQR 27-147) weeks.\n\nConclusionThis reports shows sequentially treated nAMD fellow eyes have better baseline and final VA than non-sequentially treated eyes after 2 years of treatment. Sequentially treated eyes also had a greater proportion with good VA after 2 years of treatment.\n\nPRECISDepending on age, fellow eye involvement occurs in 32% of patients with neovascular AMD by two years. Fellow eyes generally maintain better vision, except in cases where late-stage disease in the first eye was untreated.

epidemiology↗

bioRxiv2019

THE PROTO-ONCOGENE FYN INHIBITS THE ANTI-GLIOBLASTOMA IMMUNE RESPONSE

BackgroundHigh grade gliomas are aggressive and immunosuppressive brain tumors. Molecular mechanisms that regulate the inhibitory immune tumor microenvironment (TME) and glioma progression remain poorly understood. FYN tyrosine kinase is a downstream target of the oncogenic receptor tyrosine kinases pathway and is overexpressed in human gliomas. FYNs role in vivo in glioma growth remains unknown. We investigated whether FYN regulates glioma initiation, growth and invasion. MethodsWe evaluated the role of FYN using genetically engineered mouse glioma models (GEMM). We also generated FYN knockdown stem cells to induce gliomas in immune-competent and immune-deficient mice (NSG, CD8-/-, CD4-/-). We analyzed molecular mechanism by RNA-Seq and bioinformatics analysis. Flow cytometry was used to characterize immune cellular infiltrates in the FYN knockdown glioma TME. ResultsWe demonstrate that FYN knockdown in diverse immune-competent GEMMs of glioma reduced tumor progression and significantly increased survival. Gene ontologies (GOs) analysis of differentially expressed genes in wild type vs. FYN knockdown gliomas showed enrichment of GOs related to immune reactivity. However, in NSG, CD8-/- and CD4-/- immune-deficient mice, FYN knockdown gliomas failed to show differences in survival. These data suggest that the expression of FYN in glioma cells reduces anti-glioma immune activation. Examination of glioma immune infiltrates by flow-cytometry displayed reduction in the amount and activity of immune suppressive myeloid derived cells (MDSCs) in the FYN glioma TME. ConclusionsGliomas employ FYN mediated mechanisms to enhance immune-suppression and promote tumor progression. We propose that FYN inhibition within glioma cells could improve the efficacy of anti-glioma immunotherapies. Key pointsInhibition of FYN tyrosine kinase in genetically engineered mouse glioma models delays tumor initiation and progression. The oncogenic effects of FYN in vivo are mediated by downregulation of anti-glioma immunity. Importance of the StudyFYN is an effector of receptor tyrosine kinases (RTK) signaling in glioma. However, its role in vivo remains unknown. Our study demonstrates that FYN tyrosine kinase is a novel regulator of the anti-glioma immune response. We show that FYN inactivation suppresses glioma growth, increases survival, and enhances anti-tumor immune reactivity. Our findings suggest that suppressing the expression of FYN in glioma cells could provide a novel therapeutic target.

cancer biology↗

bioRxiv2019

Investigation on the effect of sonic stimulation on Xanthomonas campestris at the whole transcriptome level

A gram-negative bacterium Xanthomonas campestris was subjected to sonic stimulation with sound pertaining to 1000 Hz at three different sound intensities. The X. campestris culture subjected to sonic stimulation at 66 dB produced 1.69 fold higher exopolysaccharide. Whole transcriptome analysis of this sonic-stimulated culture revealed a total of 115 genes expressed differentially in the sonic-stimulated culture, majority of which were coding for different proteins including enzyme. This study demonstrates the property of the test bacterium of being responsive to sonic/vibrational stimulation.

microbiology↗

bioRxiv2019

Prevention of enteric bacterial infections and modulation of gut microbiota composition with conjugated linoleic acids producing Lactobacillus in mice

Probiotics are recognized to outcompete pathogenic bacteria by receptor-mediated colonizing and secreting functional metabolites which have direct antimicrobial activities towards pathogens and/or improving hosts gut health and immunity. We have constructed a Lactobacillus casei (LC) probiotic strain, LC+mcra, by inserting mcra (myosin cross-reactive antigen) gene, which stimulates the conversion of conjugated linoleic acids. In this study, we evaluated the protective roles of LC+mcra against pathogenic Salmonella enterica serovar Typhimurium (ST) and enterohaemorrhagic E. coli (EHEC) infection in BALB/cJ mice. Through a series of in vivo investigation, we observed that LC+mcra colonized efficiently in mice gut and competitively reduced the infection with ST and EHEC in various locations of small and large intestine, specifically cecum, jejunum, and ileum (p<0.05). The cecal microbiota in ST-challenged mice with LC+mcra protection were positively modulated with higher relative abundances Firmicutes but lower Proteobacteria plus increased bacterial species diversity/richness based on 16S metagenomic sequencing. Based on cytokine gene expression analysis by qRT-PCR, mice pretreated with LC+mcra were found with attenuated bacterial pathogen-induced gut inflammation. Furthermore, mice fed LC+mcra daily for one week could protect themselves from the impairments caused by enteric infections with ST or EHEC. These impairments include weight loss, negative hematological changes, intestinal histological alterations, and potential death. This in vivo study suggests that daily consumption of novel conjugated linoleic acids over-producing probiotic might be efficient in improving gut intestinal microbiome composition and preventing/combating foodborne enteric bacterial infections with pathogenic Salmonella and diarrheagenic E. coli.\n\nAuthor summaryNumerous bacteria colonize throughout the gastrointestinal tract and form a complex microbial ecosystem known as gut microbiota. A balanced microbial composition is crucial for maintaining proper gut health and host defense against pathogenic microbes. However, enteric bacterial infections could cause illness and even lead to death of host when foodborne pathogens like Salmonella and enterohaemorrhagic E. coli (EHEC) invade gut intestine and cause imbalance of gut microbiota. Beneficial microbes in gastrointestinal tract such as Lactobacillus and their secreted bio-active metabolites, are potential bio-agents to improve gut immunity and outcompete bacterial pathogens. In this study, to evaluate roles of novel Lactobacillus strain LC+mcra which produce higher amount of a group of beneficial secondary metabolites called conjugated linoleic acids, we have shown that daily oral administration of this LC+mcra for one-week in mice lead to higher proportion of beneficial bacterial colonization in different locations of intestine and a significant reduction of pathogenic Salmonella and EHEC colonization. Furthermore, mice fed with LC+mcra restore and modulate Salmonella infection-induced negative impact on gut microbiota composition and protect themselves from various levels of physiological damage.

microbiology↗

bioRxiv2019

HSV-1 single cell analysis reveals anti-viral and developmental programs activation in distinct sub-populations

Viral infection is usually studied at the population level by averaging over millions of cells. However, infection at the single-cell level is highly heterogeneous. Here, we combine live-cell imaging and single-cell RNA sequencing to characterize viral and host transcriptional heterogeneity during HSV-1 infection of primary human cells. We find extreme variability in the level of viral gene expression among individually infected cells and show that they cluster into transcriptionally distinct sub-populations. We find that anti-viral signaling is initiated in a rare group of abortively infected cells, while highly infected cells undergo cellular reprogramming to an embryonic-like transcriptional state. This reprogramming involves the recruitment of beta-catenin to the host nucleus and viral replication compartments and is required for late viral gene expression and progeny production. These findings uncover the transcriptional differences in cells with variable infection outcomes and shed new light on the manipulation of host pathways by HSV-1.

microbiology↗

bioRxiv2019

Investigating the influence of extraction methodology, and certain other experimental parameters on bacterial response to selected quorum-modulatory plant extracts

In context of the global threat of antimicrobial resistance (AMR), a large number of labs throughout the world are investigating plant extracts for their possible anti-pathogenic efficacy. Outcome of protocols employed for screening the plant extracts for such activities are influenced by multiple factors. Among them, this study has found the method used for extraction, size and volume of the assay system, to be important factors. Further we demonstrate the extracts prepared by microwave-and vacuum-assisted extraction methods to be stable with respect to their anti-pathogenic efficacy over a long period of storage.

microbiology↗

bioRxiv2018

One and Two Year Visual Outcomes from the Moorfields AMD Database - an Open Science Resource for the Study of Neovascular Age-related Macular Degeneration

ObjectivesTo analyse treatment outcomes and share clinical data from a large, single-center, well-curated database (8174 eyes / 6664 patients with 120,756 single entries) of patients with neovascular age related macular degeneration (AMD) treated with anti-vascular endothelial growth factor (VEGF). By making our depersonalised raw data openly available, we aim to stimulate further research in AMD, as well as setting a precedent for future work in this area.\n\nSettingRetrospective, comparative, non-randomised electronic medical record (EMR) database cohort study of the UK Moorfields AMD database with data extracted between 2008 and 2018.\n\nParticipants3357 eyes/patients (61% female). Extraction criteria were [≥] 1 ranibizumab or aflibercept injection, entry of \"AMD\" in the diagnosis field of the EMR, and a minimum of one year of follow-up. Exclusion criteria were unknown date of first injection and treatment outside of routine clinical care at Moorfields before the first recorded injection in the database.\n\nMain outcome measuresPrimary outcome measure was change in VA at one and two years from baseline as measured in Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Secondary outcomes were the number of injections and predictive factors for VA gain.\n\nResultsMean VA gain at one-year and two years were +5.5{+/-}0.5 and +4.9{+/-}0.68 letters respectively. Fifty-four percent of eyes gained [≥]5 letters at two years, 63% had stable VA ({+/-}[≤]14 letters), forty-four percent of eyes maintained good VA ([≥]70 letters). Patients received a mean of 7.7{+/-}0.06 injections during year one and 13.0{+/-}0.2 injections over two years.\n\nYounger age, lower baseline VA, and more injections were associated with higher VA gain at two years.\n\nConclusionThis study benchmarks high quality EMR study results of real life AMD treatment and promotes open science in clinical AMD research by making the underlying data publicly available.\n\nStrengths and limitations of this study- Large sample size, retrospective, single centre, electronic medical record database study\n- High quality real life data\n- Open science approach with sharing of depersonalised raw data

epidemiology↗

bioRxiv2018

Group Based Trajectory Analysis of Cognitive Outcomes in Children with Perinatal HIV

BackgroundCognitive impairment is common in children with perinatally-acquired HIV (pHIV). It is not known whether exposure to HIV-related neuropathogenic mechanisms during vulnerable periods of neurodevelopment may produce distinct long-term cognitive phenotypes as children age. We used group based trajectory modeling to identify clusters of children with pHIV following a unique developmental trajectory across age and predictors of belonging to select cognitive trajectory groups.\n\nMethodsParticipants included children aged 1 to 17 enrolled in the PREDICT resilience study, a cohort study of children with pHIV in Thailand and Cambodia. Cognitive testing was conducted semi-annually over three years. Group based trajectory analyses determined subgroups of children with differing cognitive trajectories using maximum likelihood estimates and Bayesian statistics. Multiple logistic regression identified baseline factors associated with belonging to the lowest scoring trajectory group.\n\nResultsThree distinct cognitive phenotypes were identified for each neurocognitive test categorized as high, medium and low scoring groups. A subgroup of children demonstrated normal developmental patterns for Color Trails Test 1 and 2. Children in the low trajectory group were more likely to present at an older age (>8 years, OR: 2.72; p 0.01) and report lower household income level (OR: 0.33-0.42; p<0.005). Neither CD4 nadir nor treatment arm was associated with cognitive trajectory status.\n\nConclusionOur study reflects the benefit of using group based trajectory modeling to classify the heterogeneity in cognitive outcomes of children with pHIV. Children were described as belonging to three distinct subgroups determined at study onset alluding to the fact that cognitive outcomes are likely to be determined at an early age with little variability over time in children with pHIV. Demographic variables, including older age at presentation and household income, were associated with low scoring cognitive trajectories, whereas HIV related variables were not. These findings mirror other studies and demonstrate the impact of socioeconomic factors on cognitive development in children with pHIV.

neuroscience↗

bioRxiv2018

Using selective lung injury to improve murine models of spatially heterogeneous lung diseases

Many lung diseases, such as acute respiratory distress syndrome (ARDS), display significant regional heterogeneity, with patches of severely injured tissue adjacent to apparently healthy tissue. Current mouse models that aim to mimic ARDS generally produce diffuse injuries that cannot reproducibly generate ARDSs regional heterogeneity. This deficiency prevents the evaluation of how well therapeutic agents reach the most injured regions, and precludes many regenerative medicine studies, since it is not possible to know which apparently healing regions suffered severe injury initially. Finally, these diffuse injury models must be mild to allow for survival, as their diffuse nature does not allow for residual healthy lung to keep an animal alive long enough for many drug and regenerative medicine studies. To solve all of these deficiencies of current animal models, we have created a simple and reproducible technique to selectively induce lung injury in specific areas of the lung. Our technique, catheter-in-catheter selective lung injury (CICSLI), involves guiding an inner catheter to a particular area of the lung and delivering an injurious agent mixed with nanoparticles (fluorescently and/or radioactively labeled) that can be used to track the location and extent of where the initial injury was, days later. Further, we demonstrate that CICSLI can produce a more severe injury than diffuse models, yet has much higher survival since CICSLI intentionally leaves undamaged lung regions. Collectively, these attributes of CICSLI will allow better study of how drugs act within heterogeneous lung pathologies and how regeneration occurs in severely damaged lung tissue, thereby aiding the development of new therapies for ARDS and other lung diseases.

pharmacology and toxicology↗