Quantifying the narrative flow of imagined versus autobiographical stories.

Lifelong experiences and learned knowledge lead to shared expectations about how common situations tend to unfold. Such knowledge of narrative event flow enables people to weave together a story. However, comparable computational tools to evaluate the flow of events in narratives are limited. We quantify the differences between autobiographical and imagined stories by introducing sequentiality, a measure of narrative flow of events, drawing probabilistic inferences from a cutting-edge large language model (GPT-3). Sequentiality captures the flow of a narrative by comparing the probability of a sentence with and without its preceding story context. We applied our measure to study thousands of diary-like stories, collected from crowdworkers, about either a recent remembered experience or an imagined story on the same topic. The results show that imagined stories have higher sequentiality than autobiographical stories and that the sequentiality of autobiographical stories increases when the memories are retold several months later. In pursuit of deeper understandings of how sequentiality measures the flow of narratives, we explore proportions of major and minor events in story sentences, as annotated by crowdworkers. We find that lower sequentiality is associated with higher proportions of major events. The methods and results highlight opportunities to use cutting-edge computational analyses, such as sequentiality, on large corpora of matched imagined and autobiographical stories to investigate the influences of memory and reasoning on language generation processes.

Implications for cumulative and prolonged clinical improvement induced by cross-linked hyaluronic acid: An in vivo biochemical/microscopic study in humans.

In photoaged human skin, type I collagen fragmentation impairs dermal extracellular matrix (ECM) integrity, resulting in collapsed/contracted fibroblasts with reduced type I procollagen synthesis. Injections of cross-linked hyaluronic acid (CL-HA) reverse these deleterious changes. To investigate the time course and effects of biochemical changes induced by injected CL-HA, particularly whether fibroblast activation leads to accumulation/deposition of dermal collagen, we injected CL-HA into photoaged skin of human participants over 60 years-old and performed biochemical/microscopic analyses of skin samples. Beginning 1 week post-injection and lasting 6-9 months, fibroblasts exhibited activation, including increased immunostaining and gene expression of markers of type I collagen synthesis, such as heat shock protein 47 and components of the transforming growth factor-ß pathway. At 1 week post-injection, multiphoton microscopy revealed elongation/stretching of fibroblasts, indicating enhanced dermal mechanical support. At 4 weeks, second-harmonic generation microscopy revealed thick collagen bundles densely packed around pools of injected CL-HA. At 12 months, accumulation of thick collagen bundles was observed and injected CL-HA remained present in substantial amounts. Thus, by occupying space in the dermal ECM, injected CL-HA rapidly and durably enhances mechanical support, stimulating fibroblast elongation and activation, which results in thick, densely packed type I collagen bundles accumulating as early as 4 weeks post-injection and continuing for at least a year. These observations indicate that early and prolonged clinical improvement following CL-HA injection results from space-filling and collagen deposition. As type I collagen has an estimated half-life of 15 years, our data provide the foundations for optimizing the timing/frequency of repeat CL-HA injections.

Acceptability of patient-centered, multi-disciplinary medication therapy management recommendations: results from the INCREASE randomized study.

BACKGROUND: Polypharmacy and inappropriate medications may be a modifiable risk factor for Alzheimer's Disease and Related Dementias (ADRD). Medication therapy management (MTM) interventions may mitigate medication-induced cognitive dysfunction and delay onset of symptomatic impairment. The objective of the current study is to describe an MTM protocol for a patient-centered team intervention (pharmacist and non-pharmacist clinician) in a randomized controlled trial (RCT) directed at delaying the symptomatic onset of ADRD. METHODS: Community dwelling adults 65 + years, non-demented, using ≥ 1 potentially inappropriate medications (PIM) were enrolled in an RCT to evaluate the effect of an MTM intervention on improving medication appropriateness and cognition (NCT02849639). The MTM intervention involved a three-step process: (1) pharmacist identified potential medication-related problems (MRPs) and made initial recommendations for prescribed and over-the-counter medications, vitamins, and supplements; (2) study team reviewed all initial recommendations together with the participants, allowing for revisions prior to the finalized recommendations; (3) participant responses to final recommendations were recorded. Here, we describe initial recommendations, changes during team engagement, and participant responses to final recommendations. RESULTS: Among the 90 participants, a mean 6.7 ± 3.6 MRPs per participant were reported. Of the 259 initial MTM recommendations made for the treatment group participants (N = 46), 40% percent underwent revisions in the second step. Participants reported willingness to adopt 46% of final recommendations and expressed need for additional primary care input in response to 38% of final recommendations. Willingness to adopt final recommendations was highest when therapeutic switches were offered and/or with anticholinergic medications. CONCLUSION: The evaluation of modifications to MTM recommendations demonstrated that pharmacists' initial MTM recommendations often changed following the participation in the multidisciplinary decision-making process that incorporated patient preferences. The team was encouraged to see a correlation between engaging patients and a positive overall response towards participant acceptance of final MTM recommendations. TRIAL REGISTRATION: Study registration number: clinicaltrial.gov NCT02849639 registered on 29/07/2016.

Acute Effects of 3 Neuromuscular Electrical Stimulation Waveforms on Exercising and Recovery Microvascular Oxygenation Responses.

CONTEXT: When emphasizing muscular strength during postoperative rehabilitation it is recommended to use a neuromuscular electrical stimulation (NMES) waveform that elicits the greatest muscle force and local metabolic demand that is also well tolerated. The present investigation examined the effects that 3 different clinically used NMES waveforms had on the electrically elicited force (EEF), local metabolic demand (exercising muscle oxygen saturation [SmO2]), and the subsequent reactive hyperemia response (recovery total hemoglobin concentration [THb]) of the knee extensors. DESIGN: Single session repeated-measures design. METHODS: EEF, local metabolic demand, and reactive hyperemia responses were measured during and subsequent to 3 NMES waveforms: Russian burst modulated alternating current (RUS), biphasic pulsed current (VMS™), and burst modulated biphasic pulsed current (VMS-Burst™). Exercising SmO2 and recovery THb were assessed noninvasively using a near-infrared spectroscopy sensor placed on the vastus lateralis. Participants completed one set of 10 repetitions of each NMES waveform and were provided with 5 minutes of passive, interset recovery. Two-way, repeated-measures analysis of variance examined if NMES waveform or repetition significantly affected (P < .05) EEF or exercising SmO2. Two-way, repeated-measures analysis of variance examined if NMES waveform or recovery time affected recovery THb. RESULTS: VMS™ and VMS-Burst™ yielded higher EEF (F = 11.839, P < .001) and greater local metabolic stress (lower exercising SmO2, F = 13.654, P < .001) compared with RUS. Greater rate of EEF decline throughout the NMES set was observed during RUS (%Δ = -50 [6] %Rep1) compared with VMS-Burst™ (%Δ = -30 [7] %Rep1) and VMS™ (%Δ = -32 [7] %Rep1). VMS™ elicited a higher reactive hyperemia response (higher recovery THb) compared with RUS (F = 3.427, P = .048). CONCLUSIONS: The present findings support the use of VMS™ or VMS-Burst™ compared with RUS when promoting muscular strength. In addition, the use of VMS™ might provide a greater blood volume to the target muscle subsequent to NMES contractions compared with RUS.

Primary Cutaneous Umbilical Melanoma: The Michigan Experience.

BACKGROUND: Primary cutaneous umbilical melanoma is rare. Thorough information regarding its characteristics and treatment, including use of sentinel lymph node biopsy (SLNB) staging, is difficult to obtain. The unique anatomy of the umbilicus adds to the complexity of diagnosing and treating melanoma at this site. OBJECTIVE: To improve understanding of diagnosis and treatment of primary cutaneous umbilical melanoma through presenting 7 new cases and reviewing 39 cases in the literature. MATERIALS AND METHODS: The University of Michigan melanoma database query and review of the literature regarding reported cases of primary umbilical melanoma. RESULTS: In 7 new and 39 previously reported cases of primary cutaneous umbilical melanoma, we describe signs and symptoms, histopathologic features, differential diagnosis, relevant anatomical considerations, and definitive treatment including SLNB when applicable. CONCLUSION: Our series, combined with a thorough literature review and compilation of findings, provides a better understanding and appreciation of melanoma in the unique anatomical site of the umbilicus, with a reminder to carefully examine the umbilicus during a full skin examination in patients at risk of melanoma. Primary umbilical melanoma presents and can be appropriately treated similarly to cutaneous melanoma in other sites, with attention to relevant anatomy.

Mohs Surgery versus Standard Local Excision for Basal Cell Carcinoma, Squamous Cell Carcinoma, and Melanoma Skin Cancer.

Basal cell carcinoma, squamous cell carcinoma, and melanoma represent the three most common skin cancers that occur on the face. The most common surgical treatments for facial skin cancers are Mohs' surgery and standard local excision. The effective utilization of either of these techniques is based on tumor and patient risk stratification incorporating known risk factors for occult invasion and local recurrence, combined with patient comorbidities, expectations, and desires. Best available evidence highlights multiple and consistent risk factors for each specific skin cancer type, and dictate local control rates reported in the literature. Recognizing gaps in the literature, we compare and review surgical treatment guidelines and data for standard local excision versus Mohs' surgery for cutaneous nonmelanoma and melanoma skin cancer. This article serves as a resource for optimal therapeutic decision making for surgical management of skin cancer on the face.

Mobilization of Telepsychiatry in Response to COVID-19-Moving Toward 21st Century Access to Care.

The COVID-19 pandemic threatens to disrupt the provision of mental health services. In response, policymakers, administrators, and providers have taken bold steps toward enabling telepsychiatry to bridge this sudden gap in care for our most vulnerable populations. With rapid deregulation and adoption of this modality of care, careful consideration of issues related to policy and implementation is essential to maximize its effectiveness and mitigate unintended consequences. Though the crisis places the healthcare system under strain, it sets the stage for a lasting shift in not only how care is delivered, but also our beliefs around the system's capacity for rapid, innovative change.

Enhanced Hydrogen Evolution in Neutral Water Catalyzed by a Cobalt Complex with a Softer Polypyridyl Ligand.

To explore the structure-function relationships of cobalt complexes in the catalytic hydrogen evolution reaction (HER), we studied the substitution of a tertiary amine with a softer pyridine group and the inclusion of a conjugated bpy unit in a Co complex with a new pentadentate ligand, 6-[6-(1,1-di-pyridin-2-yl-ethyl)-pyridin-2-ylmethyl]-[2,2']bipyridinyl (Py3Me-Bpy). These modifications resulted in significantly improved stability and activity in both electro- and photocatalytic HER in neutral water. [Co(Py3Me-Bpy)(OH2 )](PF6 )2 catalyzes the electrolytic HER at -1.3 V (vs. SHE) for 20 hours with a turnover number (TON) of 266 300, and photolytic HER for two days with a TON of 15 000 in pH 7 aqueous solutions. The softer ligand scaffold possibly provides increased stability towards the intermediate CoI species. DFT calculations demonstrate that HER occurs through a general electron transfer/proton transfer/electron transfer/proton transfer pathway, with H2 released from the protonation of CoII -H species.

The utilization of fluorescence to identify the components of lipofuscin by imaging mass spectrometry.

Lipofuscin, an aging marker in the retinal pigment epithelium (RPE) associated with the development of age-related macular degeneration, is primarily characterized by its fluorescence. The most abundant component of RPE lipofuscin is N-retinylidene-N-retinylethanolamine (A2E) but its exact composition is not known due to the complexity of the RPE extract. In this study, we utilized MALDI imaging to find potential molecules responsible for lipofuscin fluorescence in RPE tissue from Abca4(-/-) , Sv129, and C57Bl6/J mice aged 2 and 6 months. To assert relationships, the individual images in the MALDI imaging datasets were correlated with lipofuscin fluorescence recorded from the same tissues following proper registration. Spatial correlation information, which is usually lost in bioanalytics, pinpointed a relatively small number of potential lipofuscin components. The comparison of four samples in each condition further limited the possibility of false positives and provided various new, age- and strain-specific targets. Validating the usefulness of the fluorescence-enhanced imaging strategy, many known adducts of A2E were identified in the short list of lipofuscin components. These results provided evidence that mass spectrometric imaging can be utilized as a tool to begin to identify the molecular substructure of clinically-relevant diagnostic information.

Drug disposal deserts: An assessment of receptacle availability in Kentucky community pharmacies.

PURPOSE: The purpose of this study was to describe the county-level availability of drug disposal receptacles in Kentucky community pharmacies and show the relationship between installed receptacles and opioid analgesic (OA)/controlled substance dispensing rates, stratifying where possible by urban-rural classification. METHODS: Using 2020 data from the Kentucky All Schedule Prescription Electronic Reporting program and disposal receptacle data from the US Drug Enforcement Agency, county-level comparisons were made between number of receptacles and OA/controlled substance dispensing rates. Logistic and negative binomial regression models were used to assess for differences between rural/urban county designation and odds of ≥1 disposal receptacle and compare the rates of receptacles per dispensed OA dose in rural/urban counties. FINDINGS: While rural counties saw higher OA and controlled substance dispensing rates, the majority (55.6%) of disposal receptacles were in urban locations. The odds of having at least 1 receptacle were higher in urban counties (OR 2.60, 95% CI: 1.15, 5.92) compared to rural. The estimated rate of disposal receptacles per million dispensed OA doses was found to be 0.47 (95% CI: 0.36, 0.61) in urban counties compared to 0.32 (95% CI: 0.25, 0.42) in rural counties, with an estimated rate ratio of 1.45 (95% CI: 1.01, 2.10). CONCLUSIONS: A mismatch between the availability of county-level disposal receptacles in community pharmacies and the volume of dispensed OAs/controlled substances exists, resulting in fewer receptacles per dispensed OA in rural counties compared to urban counties. Future efforts are necessary to increase access to convenient disposal receptacles located in community pharmacies, particularly in rural communities.

KF4 anti-CELA1 Antibody and Purified α1-Antitrypsin Have Similar but Not Additive Efficacy in Preventing Emphysema in Murine α1-Antitrypsin Deficiency.

Alpha-1 antitrypsin (AAT) deficiency is the most common genetic cause of emphysema. Chymotrypsin-like Elastase 1 (CELA1) is a serine protease neutralized by AAT and is important in emphysema progression. Cela1-deficiency is protective in a murine models of AAT-deficient emphysema. KF4 anti-CELA1 antibody prevented emphysema in PPE and cigarette smoke models in wild type mice. We evaluated potential toxicities of KF4 and its ability to prevent emphysema in AAT deficiency. We found Cela1 protein expression in mouse lung, pancreas, small intestine, and spleen. In toxicity studies, mice treated with KF4 25 mg/kg weekly for four weeks showed an elevation in blood urea nitrogen and slower weight gain compared to lower doses or equivalent dose IgG. In histologic grading of tissue injury of the lung, kidney, liver, and heart, there was some evidence of liver injury with KF4 25 mg/kg, but in all tissues, injury was less than in control mice subjected to cecal ligation and puncture. In efficacy studies, KF4 doses as low as 0.5 mg/kg reduced the lung elastase activity of AAT-/- mice treated with 0.2 units of PPE. In this injury model, AAT-/- mice treated with KF4 1 mg/kg weekly, human purified AAT 60 mg/kg weekly, and combined KF4 and AAT treatment had less emphysema than mice treated with IgG 1 mg/kg weekly. However, the efficacy of KF4, AAT, or KF4 & AAT was similar. While KF4 might be an alternative to AAT replacement, combined KF4 and AAT replacement does not confer additional benefit.

All of whom? Limitations encountered using All of Us Researcher Workbench in a Primary Care residents secondary data analysis research training block.

OBJECTIVES: The goal of this case report is to detail experiences and challenges experienced in the training of Primary Care residents in secondary analysis using All of Us Researcher Workbench. At our large, urban safety net hospital, Primary Care/Internal Medicine residents in their third year undergo a research intensive block, the Research Practicum, where they work as a team to conduct secondary data analysis on a dataset with faculty facilitation. In 2023, this research block focused on use of the All of Us Researcher Workbench for secondary data analysis. MATERIALS AND METHODS: Two groups of 5 residents underwent training to access the All of Us Researcher Workbench, and each group explored available data with a faculty facilitator and generated original research questions. Two blocks of residents successfully completed their research blocks and created original presentations on "social isolation and A1C" levels and "medical discrimination and diabetes management." RESULTS: Departmental faculty were satisfied with the depth of learning and data exploration. In focus groups, some residents noted that for those without interest in performing research, the activity felt extraneous to their career goals, while others were glad for the opportunity to publish. In both blocks, residents highlighted dissatisfaction with the degree to which the All of Us Researcher Workbench was representative of patients they encounter in a large safety net hospital. DISCUSSION: Using the All of Us Researcher Workbench provided residents with an opportunity to explore novel questions in a massive data source. Many residents however noted that because the population described in the All of Us Researcher Workbench appeared to be more highly educated and less racially diverse than patients they encounter in their practice, research may be hard to generalize in a community health context. Additionally, given that the data required knowledge of 1 of 2 code-based data analysis languages (R or Python) and work within an idiosyncratic coding environment, residents were heavily reliant on a faculty facilitator to assist with analysis. CONCLUSION: Using the All of Us Researcher Workbench for research training allowed residents to explore novel questions and gain first-hand exposure to opportunities and challenges in secondary data analysis.

Anti-CELA1 antibody KF4 prevents emphysema by inhibiting stretch-mediated remodeling.

There are no therapies to prevent emphysema progression. Chymotrypsin-like elastase 1 (CELA1) is a serine protease that binds and cleaves lung elastin in a stretch-dependent manner and is required for emphysema in a murine antisense oligonucleotide model of α-1 antitrypsin (AAT) deficiency. This study tested whether CELA1 is important in strain-mediated lung matrix destruction in non-AAT-deficient emphysema and the efficacy of CELA1 neutralization. Airspace simplification was quantified after administration of tracheal porcine pancreatic elastase (PPE), after 8 months of cigarette smoke (CS) exposure, and in aging. In all 3 models, Cela1-/- mice had less emphysema and preserved lung elastin despite increased lung immune cells. A CELA1-neutralizing antibody was developed (KF4), and it inhibited stretch-inducible lung elastase in ex vivo mouse and human lung and immunoprecipitated CELA1 from human lung. In mice, systemically administered KF4 penetrated lung tissue in a dose-dependent manner and 5 mg/kg weekly prevented emphysema in the PPE model with both pre- and postinjury initiation and in the CS model. KF4 did not increase lung immune cells. CELA1-mediated lung matrix remodeling in response to strain is an important contributor to postnatal airspace simplification, and we believe that KF4 could be developed as a lung matrix-stabilizing therapy in emphysema.

Loss-of-function mutation in PRMT9 causes abnormal synapse development by dysregulation of RNA alternative splicing.

Protein arginine methyltransferase 9 (PRMT9) is a recently identified member of the PRMT family, yet its biological function remains largely unknown. Here, by characterizing an intellectual disability associated PRMT9 mutation (G189R) and establishing a Prmt9 conditional knockout (cKO) mouse model, we uncover an important function of PRMT9 in neuronal development. The G189R mutation abolishes PRMT9 methyltransferase activity and reduces its protein stability. Knockout of Prmt9 in hippocampal neurons causes alternative splicing of ~1900 genes, which likely accounts for the aberrant synapse development and impaired learning and memory in the Prmt9 cKO mice. Mechanistically, we discover a methylation-sensitive protein-RNA interaction between the arginine 508 (R508) of the splicing factor 3B subunit 2 (SF3B2), the site that is exclusively methylated by PRMT9, and the pre-mRNA anchoring site, a cis-regulatory element that is critical for RNA splicing. Additionally, using human and mouse cell lines, as well as an SF3B2 arginine methylation-deficient mouse model, we provide strong evidence that SF3B2 is the primary methylation substrate of PRMT9, thus highlighting the conserved function of the PRMT9/SF3B2 axis in regulating pre-mRNA splicing.

A titratable murine model of progressive emphysema using tracheal porcine pancreatic elastase.

Progressive emphysema often leads to end-stage lung disease. Most mouse models of emphysema are typically modest (i.e. cigarette smoke exposure), and changes over time are difficult to quantify. The tracheal porcine pancreatic elastase model (PPE) produces severe injury, but the literature is conflicted as to whether emphysema improves, is stable, or progresses over time. We hypothesized a threshold of injury below which repair would occur and above which emphysema would be stable or progress. We treated 8-week-old C57BL6 mixed sex mice with 0, 0.5, 2, or 4 activity units of PPE in 100 µL PBS and performed lung stereology at 21 and 84 days. There were no significant differences in weight gain or mouse health. Despite minimal emphysema at 21-days in the 0.5 units group (2.8 µm increased mean linear intercept, MLI), MLI increased by 4.6 µm between days 21 and 84 (p = 0.0007). In addition to larger MLI at 21 days in 2- and 4-unit groups, MLI increases from day 21 to 84 were 17.2 and 34 µm respectively (p = 0.002 and p = 0.0001). Total lung volume increased, and alveolar surface area decreased with time and injury severity. Contrary to our hypothesis, we found no evidence of alveolar repair over time. Airspace destruction was both progressive and accelerative. Future mechanistic studies in lung immunity, mechano-biology, senescence, and cell-specific changes may lead to novel therapies to slow or halt progressive emphysema in humans.

CELA1 Mediates Progressive Emphysema in Alpha-1 Antitrypsin Deficiency.

Chymotrypsin-like elastase 1 ( CELA1 ) is a serine protease that is neutralized by α1-antitrypsin (AAT) and prevents emphysema in a murine antisense oligonucleotide model of AAT-deficient emphysema. Mice with genetic ablation of AAT do not have emphysema at baseline but develop emphysema with injury and aging. We tested the role of CELA1 in emphysema development in this genetic model of AAT -deficiency following tracheal lipopolysacharide (LPS), 8 months of cigarette smoke (CS) exposure, aging, and a low-dose tracheal porcine pancreatic elastase (LD-PPE) model. In this last model, we performed proteomic analysis to understand differences in lung protein composition. We were unable to show that AAT -/ - mice developed more emphysema than wild type with LPS. In the LD-PPE model, AAT -/- mice developed progressive emphysema from which Cela1 -/- &AAT -/- mice were protected. In the CS model, Cela1 -/- &AAT -/- mice had worse emphysema than AAT -/- , and in the aging model, 72-75 week-old Cela1 -/- &AAT -/- mice had less emphysema than AAT -/- mice. Proteomic analysis of AAT -/- vs. wildtype lungs in the LD-PPE model showed reduced amounts of AAT proteins and increased amounts of proteins related to Rho and Rac1 GTPases and protein oxidation. Similar analysis of Cela1 -/- &AAT -/- vs. AAT -/- lungs showed differences in neutrophil degranulation, elastin fiber synthesis, and glutathione metabolism. Thus, Cela1 prevents post-injury emphysema progression in AAT -deficiency, but it has no effect and potentially worsens emphysema in response to chronic inflammation and injury. Prior to developing anti-CELA1 therapies for AAT-deficient emphysema, an understanding of why and how CS exacerbates emphysema in Cela1 deficiency is needed.

TEQUILA-seq: a versatile and low-cost method for targeted long-read RNA sequencing.

Long-read RNA sequencing (RNA-seq) is a powerful technology for transcriptome analysis, but the relatively low throughput of current long-read sequencing platforms limits transcript coverage. One strategy for overcoming this bottleneck is targeted long-read RNA-seq for preselected gene panels. We present TEQUILA-seq, a versatile, easy-to-implement, and low-cost method for targeted long-read RNA-seq utilizing isothermally linear-amplified capture probes. When performed on the Oxford nanopore platform with multiple gene panels of varying sizes, TEQUILA-seq consistently and substantially enriches transcript coverage while preserving transcript quantification. We profile full-length transcript isoforms of 468 actionable cancer genes across 40 representative breast cancer cell lines. We identify transcript isoforms enriched in specific subtypes and discover novel transcript isoforms in extensively studied cancer genes such as TP53. Among cancer genes, tumor suppressor genes (TSGs) are significantly enriched for aberrant transcript isoforms targeted for degradation via mRNA nonsense-mediated decay, revealing a common RNA-associated mechanism for TSG inactivation. TEQUILA-seq reduces the per-reaction cost of targeted capture by 2-3 orders of magnitude, as compared to a standard commercial solution. TEQUILA-seq can be broadly used for targeted sequencing of full-length transcripts in diverse biomedical research settings.

Chymotrypsin-like Elastase-1 Mediates Progressive Emphysema in Alpha-1 Antitrypsin Deficiency.

Chymotrypsin-like elastase 1 (CELA1) is a serine protease that is neutralized by alpha-1antitrypsin (AAT) and prevents emphysema in a murine antisense oligonucleotide model of AAT-deficient emphysema. Mice with genetic ablation of AAT do not have emphysema at baseline but develop emphysema with injury and aging. We tested the role of the CELA1 gene in emphysema development in this genetic model of AAT-deficiency following tracheal lipopolysaccharide (LPS), 10 months of cigarette smoke exposure, aging, and a low-dose tracheal porcine pancreatic elastase (LD-PPE) model we developed. In this last model, we performed proteomic analysis to understand differences in lung protein composition. We were unable to show that AAT-deficient mice developed more emphysema than wild type with escalating doses of LPS. In the LD-PPE model, AAT-deficient mice developed significant and progressive emphysema from which Cela1-/- & AAT-deficient mice were protected. Cela1-/-& AAT-deficient lungs had more matrix-associated proteins than AAT-deficientlungs but also had more leukocyte-associated proteases. With cigarette smoke exposure, Cela1-/- &AAT-deficient mice had more emphysema than AAT-deficient mice but had less myeloperoxidase activity. Cela1-/-&AAT-deficient mice had less age-related airspace simplification than AAT-deficient and were comparable to wild type. While CELA1 promotes inflammation-independent emphysema progression and its absence preserves the lung matrix in multiple models of AAT-deficient emphysema, for unclear reasons Cela1 deficiency is associated with increased emphysema with cigarette smoke. While anti-CELA1 therapies could potentially be used to prevent emphysema progression in AAT deficiency after smoking cessation, an understanding of why and how cigarette smoke exacerbates emphysema in Cela1 deficiency and whether AAT replacement therapy mitigates this effect is needed first.