The lung environment controls alveolar macrophage metabolism and responsiveness in type 2 inflammation.

Fine control of macrophage activation is needed to prevent inflammatory disease, particularly at barrier sites such as the lungs. However, the dominant mechanisms that regulate the activation of pulmonary macrophages during inflammation are poorly understood. We found that alveolar macrophages (AlvMs) were much less able to respond to the canonical type 2 cytokine IL-4, which underpins allergic disease and parasitic worm infections, than macrophages from lung tissue or the peritoneal cavity. We found that the hyporesponsiveness of AlvMs to IL-4 depended upon the lung environment but was independent of the host microbiota or the lung extracellular matrix components surfactant protein D (SP-D) and mucin 5b (Muc5b). AlvMs showed severely dysregulated metabolism relative to that of cavity macrophages. After removal from the lungs, AlvMs regained responsiveness to IL-4 in a glycolysis-dependent manner. Thus, impaired glycolysis in the pulmonary niche regulates AlvM responsiveness during type 2 inflammation.

T. Muris Infection Dynamics of a Fresh, Wild Isolate: Is the Established E Isolate Still Relevant?

For decades, parasitic worms such as Trichuris muris have been maintained in laboratory animals, providing insights into host-parasite interactions and host immune responses. The most used T. muris isolate is the E isolate, established in the laboratory in 1954. However, one concern with these model systems is the potential for laboratory-induced selection and therefore changes in host-parasite interactions. To address these concerns, we compare the E isolate with a recently isolated T. muris isolate (M isolate), established from wild house mice (Mus musculus domesticus, Isle of May, UK), in their capacity to infect laboratory mice. High dose infection of C57BL/6 mice revealed that significantly more parasites of the M isolate survived to the adult stage compared to the E isolate. Worm persistence was associated with heightened TNF-α and IL-10 secretion upon parasite-specific re-stimulation, and higher serum IgG1 and IgG2c levels, concomitant with an increase in T-bet+ and ICOS+ CD4+ T effector-memory cells. Differences in host response to the isolates were not as pronounced during low dose infection. Our study highlights the need for regular evaluation of lab-maintained parasite isolates against freshly isolated parasites to understand whether the established lab strains remain relevant model systems for our understanding of parasitic infections.

Dynamic Protective Factors Relevant to Sexual Offending.

PURPOSE OF REVIEW: Focusing on protective factors rather than risk factors potentially better aligns assessment with strengths-based treatment. We examine research into the assessment of protective factors to see whether it can play this role relative to sexual offending. RECENT FINDINGS: Structured asses sment of protective factors is well developed relative to violent offending but only recently studied relative to sexual offending. Nevertheless, multiple measures of protective factors have now been trialed with men who have committed sexual offenses and shown to predict reduced recidivism. Although research into individual scales is limited, overlapping content between scales suggests that protective factors aligning with constructs of Resilience, Adaptive Sexuality, and Prosocial Connection and Reward are all relevant to sexual offending. Protective factors relevant to sexual offending are sufficiently well identified that they can usefully be used for treatment need assessment, treatment planning during therapy, and case management. They can also make some contribution to risk assessment. The Structured Assessment of PROtective Factors against Sexual Offending (SAPROF-SO) is currently the most comprehensive measure of protective factors relevant to sexual offending.

Assembly and organization of the N-terminal region of mucin MUC5AC: Indications for structural and functional distinction from MUC5B.

Elevated levels of MUC5AC, one of the major gel-forming mucins in the lungs, are closely associated with chronic obstructive lung diseases such as chronic bronchitis and asthma. It is not known, however, how the structure and/or gel-making properties of MUC5AC contribute to innate lung defense in health and drive the formation of stagnant mucus in disease. To understand this, here we studied the biophysical properties and macromolecular assembly of MUC5AC compared to MUC5B. To study each native mucin, we used Calu3 monomucin cultures that produced MUC5AC or MUC5B. To understand the macromolecular assembly of MUC5AC through N-terminal oligomerization, we expressed a recombinant whole N-terminal domain (5ACNT). Scanning electron microscopy and atomic force microscopy imaging indicated that the two mucins formed distinct networks on epithelial and experimental surfaces; MUC5B formed linear, infrequently branched multimers, whereas MUC5AC formed tightly organized networks with a high degree of branching. Quartz crystal microbalance-dissipation monitoring experiments indicated that MUC5AC bound significantly more to hydrophobic surfaces and was stiffer and more viscoelastic as compared to MUC5B. Light scattering analysis determined that 5ACNT primarily forms disulfide-linked covalent dimers and higher-order oligomers (i.e., trimers and tetramers). Selective proteolytic digestion of the central glycosylated region of the full-length molecule confirmed that MUC5AC forms dimers and higher-order oligomers through its N terminus. Collectively, the distinct N-terminal organization of MUC5AC may explain the more adhesive and unique viscoelastic properties of branched, highly networked MUC5AC gels. These properties may generate insight into why/how MUC5AC forms a static, "tethered" mucus layer in chronic muco-obstructive lung diseases.

Morphologically intact airways in lung fibrosis have an abnormal proteome.

Honeycombing is a histological pattern consistent with Usual Interstitial Pneumonia (UIP). Honeycombing refers to cystic airways located at sites of dense fibrosis with marked mucus accumulation. Utilizing laser capture microdissection coupled mass spectrometry (LCM-MS), we interrogated the fibrotic honeycomb airway cells and fibrotic uninvolved airway cells (distant from honeycomb airways and morphologically intact) in specimens from 10 patients with UIP. Non-fibrotic airway cell specimens from 6 patients served as controls. Furthermore, we performed LCM-MS on the mucus plugs found in 6 patients with UIP and 6 patients with mucinous adenocarcinoma. The mass spectrometry data were subject to both qualitative and quantitative analysis and validated by immunohistochemistry. Surprisingly, fibrotic uninvolved airway cells share a similar protein profile to honeycomb airway cells, showing deregulation of the slit and roundabout receptor (Slit and Robo) pathway as the strongest category. We find that (BPI) fold-containing family B member 1 (BPIFB1) is the most significantly increased secretome-associated protein in UIP, whereas Mucin-5AC (MUC5AC) is the most significantly increased in mucinous adenocarcinoma. We conclude that fibrotic uninvolved airway cells share pathological features with fibrotic honeycomb airway cells. In addition, fibrotic honeycomb airway cells are enriched in mucin biogenesis proteins with a marked derangement in proteins essential for ciliogenesis. This unbiased spatial proteomic approach generates novel and testable hypotheses to decipher fibrosis progression.

Early Last Interglacial ocean warming drove substantial ice mass loss from Antarctica.

The future response of the Antarctic ice sheet to rising temperatures remains highly uncertain. A useful period for assessing the sensitivity of Antarctica to warming is the Last Interglacial (LIG) (129 to 116 ky), which experienced warmer polar temperatures and higher global mean sea level (GMSL) (+6 to 9 m) relative to present day. LIG sea level cannot be fully explained by Greenland Ice Sheet melt (∼2 m), ocean thermal expansion, and melting mountain glaciers (∼1 m), suggesting substantial Antarctic mass loss was initiated by warming of Southern Ocean waters, resulting from a weakening Atlantic meridional overturning circulation in response to North Atlantic surface freshening. Here, we report a blue-ice record of ice sheet and environmental change from the Weddell Sea Embayment at the periphery of the marine-based West Antarctic Ice Sheet (WAIS), which is underlain by major methane hydrate reserves. Constrained by a widespread volcanic horizon and supported by ancient microbial DNA analyses, we provide evidence for substantial mass loss across the Weddell Sea Embayment during the LIG, most likely driven by ocean warming and associated with destabilization of subglacial hydrates. Ice sheet modeling supports this interpretation and suggests that millennial-scale warming of the Southern Ocean could have triggered a multimeter rise in global sea levels. Our data indicate that Antarctica is highly vulnerable to projected increases in ocean temperatures and may drive ice-climate feedbacks that further amplify warming.

Attending to the Positive: A Retrospective Validation of the Structured Assessment of Protective Factors-Sexual Offence Version.

Sexual recidivism risk assessment tools focus almost exclusively on risk factors associated with increased rates of recidivism and do not attend to protective factors that might mitigate reoffense risk. The present study investigated the predictive validity of the Structured Assessment of Protective Factors - Sexual Offence version (SAPROF-SO), developed to assess hypothesised protective factors against sexual recidivism in adult males. The SAPROF-SO pilot version contains 24 items across two domains: Personal and Professionally Provided Support. SAPROF-SO scores were rated retrospectively from a review of archived case files of 210 men with convictions for child sexual offenses, using the SAPROF-SO pilot manual and a supplementary retrospective scoring guide developed for the current study. SAPROF-SO Total and Personal domain scores were significantly predictive of sexual recidivism after an average follow-up period of 12.24 years (AUC = .81), and to a lesser extent, violent and general recidivism. SAPROF-SO Total and Personal scores additionally provided significant incremental validity over Static-99R scores in the prediction of sexual recidivism. Results support the predictive validity of protective factors for reduced sexual recidivism and invite future research examining how to integrate the SAPROF-SO alongside contemporary sexual recidivism risk assessment tools.

Reliability and Factor Structure of the Sex Offender Treatment Intervention and Progress Scale.

Assessment of risk of sexual recidivism has progressed from tools containing only static factors to tools including dynamic (i.e., changeable) risk factors. The psychometric properties and factor structure of one such scale, the Sex Offender Treatment Intervention and Progress Scale (SOTIPS) were explored. Seven hundred and thirty-one men assigned probation for sexual crimes in New York City and Maricopa County, Arizona were administered SOTIPS three times: intake into probation, six months later, and six months after that. SOTIPS showed good internal consistency (Time 1 ω = .87, Time 2 ω = .89, and Time 3 ω = .91), and acceptable inter-rater reliability (for the 26 cases rated in the same month, ICC =.821). An exploratory factor analysis did not result in the original factor structure proposed by the developers; instead, SOTIPS showed two factors: sexual risk and antisocial opposition. This factor structure required the averaging of two items to avoid collinearity. SOTIPS showed temporal invariance indicating that its factor structure and its association to underlying latent variables are consistent over time.

Sputum biomarkers during acute severe asthma attacks in children-a case-control study.

AIM: To study sputum mediator profiles pattern in children with acute severe asthma, compared with stable asthma and healthy controls. The mechanisms of acute severe asthma attacks, such as biomarkers cascades and immunological responses, are poorly understood. METHODS: We conducted a prospective observational case-control study of children aged 5 to 17 years, who presented to hospital with an asthma attack. Children with stable asthma were recruited during outpatient asthma clinic visits. Control children without an asthma diagnosis were recruited from surgical wards. Sputum mediator profiles were measured, and sputum leukocyte differential cell counts were generated. RESULTS: Sputum data were available in 48 children (acute asthma; n = 18, stable asthma; n = 17, healthy controls; n = 13). Acute-phase biomarkers and neutrophil attractants such as IL-6 and its receptor, IL-8 and cytokines linked with bacterial signals, including TNF-R1 and TNF-R2, were elevated in asthma attacks versus stable asthma and healthy controls. T-cell attractant cytokines, associated with viral infections, such as CCL-5, CXCL-10 and CXCL-11, and CXCL-9 (secreted from eosinophils after a viral trigger) were also raised. CONCLUSION: Mediator profiles consistent with bacterial and viral respiratory infections, and T2 inflammation markers co-exist in the sputum of children with acute severe asthma attacks.

Why are individuals over age 60 still committed as sexually violent persons?

Civilly committed sexually violent persons (SVPs) are a select group of individuals designated as high risk for future sexual violence. Despite risk reduction in older age, SVP programs are seeing aging client populations, with many individuals remaining committed after age 60 (60+). Recent research found a sexual recidivism rate of 7.5% for 60+ individuals released from an SVP civil commitment program. The current paper follows up by examining reasons why individuals remain committed after age 60. It compares SVPs discharged after age 60 to those who are 60+ but remain civilly committed. Results of bivariate analyses reveal older SVPs who remain committed have significantly higher actuarial risk scores and are more likely to be of minority race. Multivariate logistic regression analyses found actuarial risk scores (Static-99R) predicted continued commitment, after controlling for other relevant variables. Barriers to community reintegration and suggestions for multi-disciplinary case management for older SVPs are discussed.

Hormonal response to perceived emotional distress in incarcerated men with sexual sadism.

Sexual sadists derive pleasure from humiliation, domination and infliction of pain on victims. They display increased penile arousal and activation of brain regions involved in sexual arousal and emotional states when viewing stimuli depicting individuals in physical distress. Neuroactive hormones modulate these regions, but it is unknown if sexual sadists also have endocrine responses to depictions of individuals in distress. The present study examined endocrine responses, elicited by viewing a video depicting an individual in extreme emotional distress, in incarcerated adult male sexual offenders (n = 23) with varying levels of sadistic traits. Sadism, was measured by the Severe Sexual Sadism Scale (SeSaS). Testosterone (T), adrenocorticotropic hormone (ACTH), and oxytocin (OT) were assayed before and after participants watched a video depicting an individual in emotional distress. T responses to the video were significantly and positively associated with SeSaS scores. There were no significant associations between sexual sadism and OT or ACTH. Our findings provide physiological evidence of atypical processing of distress cues in sadism consistent with the role of testosterone in sexual arousal and aggressive behaviors. These findings have implications for the evaluation and treatment of sexual sadists.

Long Term Recidivism Rates Among Individuals at High Risk to Sexually Reoffend.

Preventive detention provisions in the US and Canada assume we can identify, in advance, individuals at high risk for sexual recidivism. To test this assumption, 377 adult males with a history of sexual offending were followed for 20 years using Canadian national criminal history records and Internet searches. Using previously collected information, a high risk/high need (HRHN) subgroup was identified based on an unusually high levels of criminogenic needs (n = 190, average age of 38 years; 83% White, 13% Indigenous, 4% other). A well above average subgroup of 99 individuals was then identified based on high Static-99R (6+) and Static-2002R (7+) scores. In the HRHN group, 40% reoffended sexually. STATIC HRHN norms overestimated sexual recidivism at 5 years (Static-99R, E/O = 1.44; Static-2002R, E/O = 1.72) but were well calibrated for longer follow-up periods (20 years: Static-99R, E/0 = 1.00; Static-2002R, E/O = 1.16). The overall sexual recidivism rate for the well above average subgroup was 52.1% after 20 years, and 74.3% for any violent recidivism. The highest risk individuals (top 1%) had rates in the 60%-70% range. We conclude that some individuals present a high risk for sexual recidivism, and can be identified using currently available methods.

Understanding the Latent Structure of Dynamic Risk: Seeking Empirical Constraints on Theory Development Using the VRS-SO and the Theory of Dynamic Risk.

The present study is part of a larger project aiming to more closely integrate theory with empirical research into dynamic risk. It seeks to generate empirical findings with the dynamic risk factors contained in the Violence Risk Scale-Sexual Offense version (VRS-SO) that might constrain and guide the further development of Thornton's theoretical model of dynamic risk. Two key issues for theory development are (a) whether the structure of pretreatment dynamic risk factors is the same as the structure of the change in the dynamic risk factors that occurs during treatment, and (b) whether theoretical analysis should focus on individual dynamic items or on the broader factors that run through them. Factor analyses and item-level prediction analyses were conducted on VRS-SO pretreatment, posttreatment, and change ratings obtained from a large combined sample of men (Ns = 1,289-1,431) convicted and treated for sexual offenses. Results indicated that the latent structure of pretreatment dynamic risk was best described by a three-factor model while the latent structure of change items was two dimensional. Prediction analyses examined the degree to which items were predictive beyond prediction obtained from the broader factor that they loaded on. Results showed that for some items, their prediction appeared to be largely carried by the three broad factors. In contrast, other items seem to operate as funnels through which the broader factors' predictiveness flowed. Implications for theory development implied by these results are identified.

Trickle infection and immunity to Trichuris muris.

The majority of experiments investigating the immune response to gastrointestinal helminth infection use a single bolus infection. However, in situ individuals are repeatedly infected with low doses. Therefore, to model natural infection, mice were repeatedly infected (trickle infection) with low doses of Trichuris muris. Trickle infection resulted in the slow acquisition of immunity reflected by a gradual increase in worm burden followed by partial expulsion. Flow cytometry revealed that the CD4+ T cell response shifted from Th1 dominated to Th2 dominated, which coincided with an increase in Type 2 cytokines. The development of resistance following trickle infection was associated with increased worm expulsion effector mechanisms including goblet cell hyperplasia, Muc5ac production and increased epithelial cell turn over. Depletion of CD4+ T cells reversed resistance confirming their importance in protective immunity following trickle infection. In contrast, depletion of group 2 innate lymphoid cells did not alter protective immunity. T. muris trickle infection resulted in a dysbiotic mircrobiota which began to recover alpha diversity following the development of resistance. These data establish trickle infection as a robust and informative model for analysis of immunity to chronic intestinal helminth infection more akin to that observed under natural infection conditions and confirms the importance of CD4+ T cell adaptive immunity in host protection.

Using Lean-Facilitation to Improve Quality of Hepatitis C Testing in Primary Care.

BACKGROUND: Lean management has been successfully employed in healthcare to improve outcomes and efficiencies. Facilitation is increasingly being used to support evidence-based practice uptake in healthcare. However, while both Lean and Facilitation are used in healthcare quality improvement, limited research has explored their integration and the sustainability of their combined effects. OBJECTIVE: To improve hepatitis C virus (HCV) screening rates among persons born between 1945 and 1965 through the design and evaluation of a multi-modal Lean-Facilitation intervention (LFI) for Department of Veterans Affairs primary care community clinics. DESIGN: We conducted a mixed methods quasi-experimental evaluation in eight clinics, guided by the integrated Promoting Action on Research Implementation in Health Services framework. PARTICIPANTS: We engaged regional and local leadership (N = 9), implemented our LFI with clinicians and staff (N = 68), and conducted summative interviews with participants (N = 13). INTERVENTION: The LFI included six implementation strategies: (1) external facilitation, (2) stakeholder engagement, (3) champion activation, (4) rapid process improvement sessions, (5) Plan-Do-Study-Act cycles, and (6) audit-feedback. MEASURES: The primary outcome was rate of new HCV screening among previously untested patients with a primary care visit. Using interrupted time series, we analyzed intervention and time effects on HCV testing rates, and administered organizational readiness surveys, conducted summative qualitative interviews, and tracked facilitation events. RESULTS: The LFI was associated with significant, immediate, and sustained increases in HCV testing. No change was detected at matched comparison clinics. Staff accepted the LFI and the philosophy of "bottom-up" solution development yet had mixed feedback on its appropriateness and feasibility. Enablers of implementation and early sustainment included lower satisfaction with baseline HCV testing processes and staff culture, while later sustainment was related to implementation climate support, measurement, and evaluation. CONCLUSIONS: High-reach and relatively low effort, but persistent intervention led to significant improvement in guideline-concordant HCV testing rates which were sustained. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02936648.

Neural Correlates of Moral Judgment in Criminal Offenders with Sadistic Traits.

Sexual sadism is a paraphilia that focuses on domination, humiliation, and infliction of pain on a victim to stimulate sexual arousal. Although extensively described in psychology and forensic sciences, less is known about whether the harmful acts committed by sexual sadists are accompanied by deficits in moral judgment. A limited amount of behavioral research suggests moral insensitivity in sexual sadists; however, the neural networks underlying moral judgment in sadists have not been studied. In this pilot study, 21 incarcerated male sexual offenders with (n = 11) and without (n = 10) sexual sadism were scanned with functional magnetic resonance imaging (fMRI) while they viewed pictures that did or did not depict situations considered by most individuals to represent moral transgressions, and rated their degree of moral transgression severity. Results indicated primarily overlapping neural systems underlying moral judgment in sadists and non-sadists. However, non-sadists but not sadists showed a positive correlation between moral transgression severity ratings and activity in the anterior temporal cortex (ATC). This lack of ATC engagement in sadists might be a biomarker of altered moral judgment.

Airway Mucus Hyperconcentration in Non-Cystic Fibrosis Bronchiectasis.

Rationale: Non-cystic fibrosis bronchiectasis is characterized by airway mucus accumulation and sputum production, but the role of mucus concentration in the pathogenesis of these abnormalities has not been characterized.Objectives: This study was designed to: 1) measure mucus concentration and biophysical properties of bronchiectasis mucus; 2) identify the secreted mucins contained in bronchiectasis mucus; 3) relate mucus properties to airway epithelial mucin RNA/protein expression; and 4) explore relationships between mucus hyperconcentration and disease severity.Methods: Sputum samples were collected from subjects with bronchiectasis, with and without chronic erythromycin administration, and healthy control subjects. Sputum percent solid concentrations, total and individual mucin concentrations, osmotic pressures, rheological properties, and inflammatory mediators were measured. Intracellular mucins were measured in endobronchial biopsies by immunohistochemistry and gene expression. MUC5B (mucin 5B) polymorphisms were identified by quantitative PCR. In a replication bronchiectasis cohort, spontaneously expectorated and hypertonic saline-induced sputa were collected, and mucus/mucin concentrations were measured.Measurements and Main Results: Bronchiectasis sputum exhibited increased percent solids, total and individual (MUC5B and MUC5AC) mucin concentrations, osmotic pressure, and elastic and viscous moduli compared with healthy sputum. Within subjects with bronchiectasis, sputum percent solids correlated inversely with FEV1 and positively with bronchiectasis extent, as measured by high-resolution computed tomography, and inflammatory mediators. No difference was detected in MUC5B rs35705950 SNP allele frequency between bronchiectasis and healthy individuals. Hypertonic saline inhalation acutely reduced non-cystic fibrosis bronchiectasis mucus concentration by 5%.Conclusions: Hyperconcentrated airway mucus is characteristic of subjects with bronchiectasis, likely contributes to disease pathophysiology, and may be a target for pharmacotherapy.

Functional characterization of the mucus barrier on the Xenopus tropicalis skin surface.

Mucosal surfaces represent critical routes for entry and exit of pathogens. As such, animals have evolved strategies to combat infection at these sites, in particular the production of mucus to prevent attachment and to promote subsequent movement of the mucus/microbe away from the underlying epithelial surface. Using biochemical, biophysical, and infection studies, we have investigated the host protective properties of the skin mucus barrier of the Xenopus tropicalis tadpole. Specifically, we have characterized the major structural component of the barrier and shown that it is a mucin glycoprotein (Otogelin-like or Otogl) with similar sequence, domain organization, and structural properties to human gel-forming mucins. This mucin forms the structural basis of a surface barrier (∼6 µm thick), which is depleted through knockdown of Otogl. Crucially, Otogl knockdown leads to susceptibility to infection by the opportunistic pathogen Aeromonas hydrophila To more accurately reflect its structure, tissue localization, and function, we have renamed Otogl as Xenopus Skin Mucin, or MucXS. Our findings characterize an accessible and tractable model system to define mucus barrier function and host-microbe interactions.

Estimating Lifetime and Residual Risk for Individuals Who Remain Sexual Offense Free in the Community: Practical Applications.

Although individuals with a history of sexual crime are often viewed as a lifelong risk, recent research has drawn attention to consistent declines in recidivism risk for those who remain offense free in the community. Because these declines are predictable, this article demonstrates how evaluators can use the amount of time individuals have remained offense free to (a) extrapolate to lifetime recidivism rates from rates observed for shorter time periods, (b) estimate the risk of sexual recidivism for individuals whose current offense is nonsexual but who have a history of sexual offending, and (c) calculate yearly reductions in risk for individuals who remain offense free in the community. In addition to their practical utility for case-specific decision making, these estimates also provide researchers an objective, empirical method of quantifying the extent to which individuals have desisted from sexual crime.

The C-terminal dimerization domain of the respiratory mucin MUC5B functions in mucin stability and intracellular packaging before secretion.

Mucin 5B (MUC5B) has an essential role in mucociliary clearance that protects the pulmonary airways. Accordingly, knowledge of MUC5B structure and its interactions with itself and other proteins is critical to better understand airway mucus biology and improve the management of lung diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). The role of an N-terminal multimerization domain in the supramolecular organization of MUC5B has been previously described, but less is known about its C-terminal dimerization domain. Here, using cryogenic electron microscopy (cryo-EM) and small-angle X-ray scattering (SAXS) analyses of recombinant disulfide-linked dimeric MUC5B dimerization domain we identified an asymmetric, elongated twisted structure, with a double globular base. We found that the dimerization domain is more resistant to disruption than the multimerization domain suggesting the twisted structure of the dimerization domain confers additional stability to MUC5B polymers. Size-exclusion chromatography-multiangle light scattering (SEC-MALS), SPR-based biophysical analyses and microscale thermophoresis of the dimerization domain disclosed no further assembly, but did reveal reversible, calcium-dependent interactions between the dimerization and multimerization domains that were most active at acidic pH, suggesting that these domains have a role in MUC5B intragranular organization. In summary, our results suggest a role for the C-terminal dimerization domain of MUC5B in compaction of mucin chains during granular packaging via interactions with the N-terminal multimerization domain. Our findings further suggest that the less stable multimerization domain provides a potential target for mucin depolymerization to remove mucus plugs in COPD and other lung pathologies.