Myeloid-specific deletion of activating transcription factor 6 alpha increases CD11b+ macrophage subpopulations and aggravates lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease of unknown etiology. The accumulation of macrophages is associated with disease pathogenesis. The unfolded protein response (UPR) has been linked to macrophage activation in pulmonary fibrosis. To date, the impact of activating transcription factor 6 alpha (ATF6α), one of the UPR mediators, on the composition and function of pulmonary macrophage subpopulations during lung injury and fibrogenesis is not fully understood. We began by examining the expression of Atf6α in IPF patients' lung single-cell RNA sequencing dataset, archived surgical lung specimens, and CD14+ circulating monocytes. To assess the impact of ATF6α on pulmonary macrophage composition and pro-fibrotic function during tissue remodeling, we conducted an in vivo myeloid-specific deletion of Atf6α. Flow cytometric assessments of pulmonary macrophages were carried out in C57BL/6 and myeloid specific ATF6α-deficient mice in the context of bleomycin-induced lung injury. Our results demonstrated that Atf6α mRNA was expressed in pro-fibrotic macrophages found in the lung of a patient with IPF and in CD14+ circulating monocytes obtained from blood of a patient with IPF. After bleomycin administration, the myeloid-specific deletion of Atf6α altered the pulmonary macrophage composition, expanding CD11b+ subpopulations with dual polarized CD38+ CD206+ expressing macrophages. Compositional changes were associated with an aggravation of fibrogenesis including increased myofibroblast and collagen deposition. A further mechanistic ex vivo investigation revealed that ATF6α was required for CHOP induction and the death of bone marrow-derived macrophages. Overall, our findings suggest a detrimental role for the ATF6α-deficient CD11b+ macrophages which had altered function during lung injury and fibrosis.

Peekbank: An open, large-scale repository for developmental eye-tracking data of children's word recognition.

The ability to rapidly recognize words and link them to referents is central to children's early language development. This ability, often called word recognition in the developmental literature, is typically studied in the looking-while-listening paradigm, which measures infants' fixation on a target object (vs. a distractor) after hearing a target label. We present a large-scale, open database of infant and toddler eye-tracking data from looking-while-listening tasks. The goal of this effort is to address theoretical and methodological challenges in measuring vocabulary development. We first present how we created the database, its features and structure, and associated tools for processing and accessing infant eye-tracking datasets. Using these tools, we then work through two illustrative examples to show how researchers can use Peekbank to interrogate theoretical and methodological questions about children's developing word recognition ability.

Streptococcus salivarius inhibits immune activation by periodontal disease pathogens.

BACKGROUND: Periodontal disease represents a major health concern. The administration of beneficial microbes has been increasing in popularity over efforts to manipulate the microbes using antimicrobial agents. This study determined the ability of Streptococcus salivarius to inhibit IL-6 and IL-8 production by gingival fibroblasts when activated by periodontal pathogens and their effect on the salivary microbiome. METHODS: Primary human gingival fibroblasts were challenged with Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans and Fusobacterium nucleatum and a combination of all three. IL-6 and IL-8 cytokine release were measured. Using this same model, S. salivarius K12, M18 and different supernatant and whole-cell lysate fractions of S. salivarius K12 were administered to pathogen-induced fibroblasts. A patient study of healthy participants was also conducted to determine the effect S. salivarius K12 had on the native microbiome using 16S next generation sequence analysis. RESULTS: All pathogens tested induced a significant IL-6 and IL-8 response. S. salivarius K12 or M18, did not exhibit an increase in inflammatory cytokines. When either of the probiotic strains were co-administered with a pathogen, there were significant reductions in both IL-6 and IL-8 release. This effect was also observed when gingival fibroblasts were pre-treated with either S. salivarius K12 or M18 and then stimulated with the oral pathogens. Chewing gum containing S. salivarius K12 did not alter the salivary microbiome and did not increase inflammatory markers in the oral cavity. CONCLUSION: S. salivarius K12 and M18 prevented immune activation induced by periodontal disease pathogens. S. salivarius K12 did not alter the salivary microbiome or induce immune activation when administered as a chewing gum. These results warrant further study to determine if it may be an effective treatment in a model of periodontal disease.

childes-db: A flexible and reproducible interface to the child language data exchange system.

The Child Language Data Exchange System (CHILDES) has played a critical role in research on child language development, particularly in characterizing the early language learning environment. Access to these data can be both complex for novices and difficult to automate for advanced users, however. To address these issues, we introduce childes-db, a database-formatted mirror of CHILDES that improves data accessibility and usability by offering novel interfaces, including browsable web applications and an R application programming interface (API). Along with versioned infrastructure that facilitates reproducibility of past analyses, these interfaces lower barriers to analyzing naturalistic parent-child language, allowing for a wider range of researchers in language and cognitive development to easily leverage CHILDES in their work.

Real-time lexical comprehension in young children learning American Sign Language.

When children interpret spoken language in real time, linguistic information drives rapid shifts in visual attention to objects in the visual world. This language-vision interaction can provide insights into children's developing efficiency in language comprehension. But how does language influence visual attention when the linguistic signal and the visual world are both processed via the visual channel? Here, we measured eye movements during real-time comprehension of a visual-manual language, American Sign Language (ASL), by 29 native ASL-learning children (16-53 mos, 16 deaf, 13 hearing) and 16 fluent deaf adult signers. All signers showed evidence of rapid, incremental language comprehension, tending to initiate an eye movement before sign offset. Deaf and hearing ASL-learners showed similar gaze patterns, suggesting that the in-the-moment dynamics of eye movements during ASL processing are shaped by the constraints of processing a visual language in real time and not by differential access to auditory information in day-to-day life. Finally, variation in children's ASL processing was positively correlated with age and vocabulary size. Thus, despite competition for attention within a single modality, the timing and accuracy of visual fixations during ASL comprehension reflect information processing skills that are important for language acquisition regardless of language modality.

Social cues modulate the representations underlying cross-situational learning.

Because children hear language in environments that contain many things to talk about, learning the meaning of even the simplest word requires making inferences under uncertainty. A cross-situational statistical learner can aggregate across naming events to form stable word-referent mappings, but this approach neglects an important source of information that can reduce referential uncertainty: social cues from speakers (e.g., eye gaze). In four large-scale experiments with adults, we tested the effects of varying referential uncertainty in cross-situational word learning using social cues. Social cues shifted learners away from tracking multiple hypotheses and towards storing only a single hypothesis (Experiments 1 and 2). In addition, learners were sensitive to graded changes in the strength of a social cue, and when it became less reliable, they were more likely to store multiple hypotheses (Experiment 3). Finally, learners stored fewer word-referent mappings in the presence of a social cue even when given the opportunity to visually inspect the objects for the same amount of time (Experiment 4). Taken together, our data suggest that the representations underlying cross-situational word learning of concrete object labels are quite flexible: In conditions of greater uncertainty, learners store a broader range of information.

Efficacy of Dentaq® Oral and ENT Health Probiotic Complex on Clinical Parameters of Gingivitis in Patients Undergoing Fixed Orthodontic Treatment: A Pilot Study.

OBJECTIVES: Probiotics act as a unique approach to maintaining oral health by supplementing the endogenous oral bacteria with additional naturally occurring beneficial microbes to provide defense against pathogens harmful to teeth and gingiva. The aim of this pilot study was to clinically evaluate the effects of probiotics on plaque accumulation and gingival inflammation in subjects with fixed orthodontics. METHODS: The pilot study was comprised of 15 healthy patients, aged 11 to 18 years, undergoing fixed orthodontic treatment. Patients used an all-natural, dissolving lozenge containing six proprietary probiotic strains (Dentaq® Oral and ENT Health Probiotic Complex)for 28 days. Gingival Index (GI) according to Löe-Silness and Plaque Index (PI) according to Quigley-Hein for all teeth were measured at baseline (Day Zero) and at the end of the probiotic regimen (Day 28). RESULTS: The mean baseline GI and PI scores within each patient decreased by 28.4% and 35.8%, respectively, by Day 28. Patients reported decreased tooth and gingival pain, decreased oral bleeding, and increased motivation to maintain proper oral hygiene over the course of the study. CONCLUSIONS: This pilot study provided preliminary support for the use of Dentaq Oral and ENT Health Probiotic Complex as a safe and effective natural health product for the reduction of plaque accumulation and gingival inflammation. The results demonstrate its potential therapeutic value and open the door for larger scale placebo-controlled clinical studies to verify these findings.

Selective target inactivation rather than global metabolic dormancy causes antibiotic tolerance in uropathogens.

Persister cells represent a multidrug-tolerant (MDT), physiologically distinct subpopulation of bacteria. The ability of these organisms to survive lethal antibiotic doses raises concern over their potential role in chronic disease, such as recurrent urinary tract infection (RUTI). Persistence is believed to be conveyed through global metabolic dormancy, which yields organisms unresponsive to external stimuli. However, recent studies have contested this stance. Here, various antibiotics that target different cellular processes were used to dissect the activity of transcription, translation, and peptidoglycan turnover in persister cells. Differential susceptibility patterns were found in type I and type II persisters, and responses differed between Staphylococcus saprophyticus and Escherichia coli uropathogens. Further, SOS-deficient strains were sensitized to ciprofloxacin, suggesting DNA gyrase activity in persisters and indicating the importance of active DNA repair systems for ciprofloxacin tolerance. These results indicate that global dormancy per se cannot sufficiently account for antibiotic tolerance. Rather, the activity of individual cellular processes dictates multidrug tolerance in an antibiotic-specific fashion. Furthermore, the susceptibility patterns of persisters depended on their mechanisms of onset, with subinhibitory antibiotic pretreatments selectively shutting down cognate targets and increasing the persister fraction against the same agent. Interestingly, antibiotics targeting transcription and translation enhanced persistence against multiple agents indirectly related to these processes. Conducting these assays with uropathogenic E. coli isolated from RUTI patients revealed an enriched persister fraction compared to organisms cleared with standard antibiotic therapy. This finding suggests that persister traits are either selected for during prolonged antibiotic treatment or initially contribute to therapy failure.

Tuning the visible colour of octahedral manganese(III) phthalocyanines via axial ligand exchange.

A series of [PcMnL2]SbF6 complexes (Pc = phthalocyanine) was synthesized and structurally characterized by stripping the chloride from PcMnCl with AgSbF6 in o-dichlorobenzene and adding a range of donor ligands (L = THF, pyridine, p-dimethylaminopyridine (DMAP), Ph3PO, N-methylimidazole (MeIm), MeCN) to the resulting solution. Addition of or exposure to water where L = heterocyclic amines yielded µ-oxo complexes of the form [PcMnL]2O, which were structurally characterized for L = DMAP and MeIm. The [PcMnL2]SbF6 complexes have an increased solubility in organic solvents, where the axial ligands inhibit the characteristic ring π-π aggregation of PcM complexes. A variety of colours were observed (blue/green to red/purple), with Q-band absorptions (excluding the µ-oxo species) spanning from 715-761 nm and LMCT-bands from 497-574 nm. The combination of the ligand-induced absorption shifts coupled with their relative intensities in the visible region is responsible for the observed colour range and illustrates that facile ligand exchange is a useful tool in producing materials with a variety of colours from PcMnCl.

UAS™-A Urine Preservative for Oncology Applications.

Liquid biopsy is a revolutionary tool that is gaining momentum in the field of cancer research. As a body fluid, urine can be used in non-invasive diagnostics for various types of cancer. We investigated the performance of UAS™ as a preservative for urinary analytes. Firstly, the need for urine preservation was investigated using urine samples from healthy volunteers. Secondly, the performance of UAS™ was assessed for cell-free DNA (cfDNA) and host cell integrity during storage at room temperature (RT) and after freeze-thaw cycling. Finally, UAS™ was used in a clinical setting on samples from breast and prostate cancer patients. In the absence of a preservative, urinary cfDNA was degraded, and bacterial overgrowth occurred at RT. In urine samples stored in UAS™, no microbial growth was seen, and cfDNA and cellular integrity were maintained for up to 14 days at RT. After freeze-thaw cycling, the preservation of host cell integrity and cfDNA showed significant improvements when using UAS™ compared to unpreserved urine samples. Additionally, UAS™ was found to be compatible with several commercially available isolation methods.

The use of triclosan eluting stents effectively reduces ureteral stent symptoms: a prospective randomized trial.

UNLABELLED: What's known on the subject? and What does the study add? Infection, encrustation and ureteral-stent-related symptoms (USRS) including pain, urgency and frequency are all major problems associated with stent use. No current ureteral stent or exogenously applied therapy adequately deals with these problems and antibiotic use is ineffective once a bacterial biofilm forms on the device. Triclosan is a broad spectrum antibacterial agent widely used in numerous healthcare products and has been previously shown to reduce inflammation on the skin and in the oral cavity. This study tested a triclosan-impregnated ureteral stent for its ability to reduce infection, encrustation and USRS. This study shows that while a triclosan-impregnated ureteral stent cannot reduce infection rates alone compared with antibiotic use, the stent can reduce several USRS including pain during indwelling. This study suggests that the triclosan eluting stent may have a role in treating patients, perhaps in combination with standard antibiotic therapy. OBJECTIVE: To evaluate the capacity of triclosan-loaded ureteral stents to reduce stent-associated bacterial attachment, biofilm formation and encrustation, thereby potentially reducing infection development and other device-related sequelae. PATIENTS AND METHODS: Twenty subjects requiring short-term stenting (7-15 days) were randomized to receive either a Percuflex Plus(®) non-eluting stent (control) or a Triumph(®) triclosan eluting stent. Control-stented subjects received 3 days of levofloxacin prophylaxis (500 mg once daily) while Triumph(®)-stented subjects did not. All subjects were assessed for positive urine and stent cultures, stent biofilm development and encrustation. Following device removal, each subject completed an analogue-scale symptom assessment questionnaire. RESULTS: Ureteral stenting was performed after nine ureteroscopic and one extracorporeal shock wave lithotripsy procedure in the control group and eight ureteroscopic and two shock wave lithotripsy procedures in the triclosan group. No significant differences were observed for culture, biofilm and encrustation between the two groups. Subjects in the triclosan group reported significant reductions in lower flank pain scores during activity (58.1% reduction, P = 0.017) and urination (42.6%, P = 0.041), abdominal pain during activity (42.1%, P = 0.042) and urethral pain during urination (31.7%, P = 0.049). CONCLUSIONS: In this study, the use of the Triumph(®) triclosan eluting stent had no marked impact on biofilm formation, encrustation or infection development in short-term stented patients. The Triumph(®) device led to significant reductions in several common ureteral-stent-related symptoms, supporting its use in this patient population.

Type I Interferon Signaling is Required for Oncostatin-M Driven Inflammatory Responses in Mouse Lung.

Type I interferons (IFNs) consist of a group of structurally similar cytokines that play an integral role in regulating the immune response to combat lung infections. In certain models type I IFNs have also been associated with suppression of Th2-skewed immune and inflammatory responses. Transient pulmonary overexpression of the gp130 cytokine Oncostatin M (OSM) by Adenovirus vector (AdOSM) induces a robust Th2-skewed cytokine/inflammatory profile in C57Bl/6 murine lungs. In this study we assessed type I IFN function in OSM-mediated inflammation in vivo using Ifnar1-/- C57Bl/6 mice and Ifnar1-deficient cells in vitro. Ifnar1-/- mice showed a significant reduction in AdOSM-induced histopathology (epithelial hyperplasia, alveolar septal wall thickening, cellular infiltration), and levels of IL-6 and chemokine protein (CXCL-1/KC and CCL24/eotaxin-2) in lungs compared with wild-type. Ifnar1-/- murine fibroblasts and human type I IFN receptor (Ifnar)-knockdown fibroblasts were also less responsive to OSM in STAT3 activation and cytokine production compared with Ifnar-sufficient cells in vitro. Exogenous type I IFN induced IL-6 responses in mouse and human fibroblasts and in combination with OSM further stimulated IL-6 production, suggesting a concerted action of type I IFNs and OSM. Taken together, these results demonstrate that cross-talk between IFNAR and OSM signaling enhances cell responses and modulates OSM-driven responses in lung inflammation.

Effectiveness of the Lorodent Probiotic Lozenge in Reducing Plaque and Streptococcus mutans Levels in Orthodontic Patients: A Double-Blind Randomized Control Trial.

Orthodontic patients are at a significant risk for oral diseases due to increased plaque accumulation and oral bacterial dysbiosis. We aimed to determine the efficacy of the commercially available Lorodent Probiotic Complex at reducing plaque accumulation and Streptococcus mutans bacterial levels in adolescent orthodontic patients. Sixty adolescents undergoing fixed orthodontic treatment for a minimum of 6 months were recruited in a randomized, double-blind, parallel-group, placebo-controlled trial. They received either Lorodent probiotic lozenge (intervention, n = 30) or placebo lozenge (control, n = 30) orally every day for a 28-day administration period. Participants were assessed at four appointments (T1-T4) over a total of 56 days. Compliance and lozenge satisfaction were monitored. Saliva samples and supragingival plaques were collected for evaluation of S. mutans levels. Clinical assessment using a Plaque Index (PI) was used. Compliance with lozenge intake of all participants was over 90%. There was no significant change in the PI and composite PI scores in both placebo and probiotic groups at each time frame (all p > 0.05) or the relative S. mutans DNA levels in the saliva and plaque between the probiotic and placebo groups. The findings of high compliance and satisfaction with the probiotic lozenges combined with the study's rigorous design offer a baseline for subsequent testing of further potential probiotics (of varying formulations, concentrations), especially in adolescents.

Analytic reproducibility in articles receiving open data badges at the journal Psychological Science: an observational study.

For any scientific report, repeating the original analyses upon the original data should yield the original outcomes. We evaluated analytic reproducibility in 25 Psychological Science articles awarded open data badges between 2014 and 2015. Initially, 16 (64%, 95% confidence interval [43,81]) articles contained at least one 'major numerical discrepancy' (>10% difference) prompting us to request input from original authors. Ultimately, target values were reproducible without author involvement for 9 (36% [20,59]) articles; reproducible with author involvement for 6 (24% [8,47]) articles; not fully reproducible with no substantive author response for 3 (12% [0,35]) articles; and not fully reproducible despite author involvement for 7 (28% [12,51]) articles. Overall, 37 major numerical discrepancies remained out of 789 checked values (5% [3,6]), but original conclusions did not appear affected. Non-reproducibility was primarily caused by unclear reporting of analytic procedures. These results highlight that open data alone is not sufficient to ensure analytic reproducibility.

Acceptability of capnography-assisted respiratory therapy: a new mind-body intervention for COPD.

Dyspnoea self-management is often suboptimal for patients with COPD. Many patients with COPD experience chronic dyspnoea as distressing and disabling, especially during physical activities. Breathing therapy is a behavioural intervention that targets reducing the distress and impact of dyspnoea on exertion in daily living. Using a qualitative design, we conducted interviews with 14 patients after they participated in a novel mind-body breathing therapy intervention adjunct, capnography-assisted respiratory therapy (CART), combined with outpatient pulmonary rehabilitation. Comprehensive CART consisted of patient-centred biofeedback, tailored breathing exercises, a home exercise programme and motivational interviewing counselling. We assessed participants' perceptions and reported experiences to gauge the acceptability of CART and refine CART based on feedback. Constant comparative analysis was used to identify commonalities and themes. We identified three main themes relating to the acceptability and reported benefits of CART: (1) self-regulating breathing; (2) impact on health; and (3) patient satisfaction. Our findings were used to refine and optimise CART (i.e. its intensity, timing and format) for COPD. By addressing dysfunctional breathing behaviours and dysregulated interoception, CART offers a promising new paradigm for relieving dyspnoea and related anxiety in patients with COPD.

Children flexibly seek visual information to support signed and spoken language comprehension.

During grounded language comprehension, listeners must link the incoming linguistic signal to the visual world despite uncertainty in the input. Information gathered through visual fixations can facilitate understanding. But do listeners flexibly seek supportive visual information? Here, we propose that even young children can adapt their gaze and actively gather information for the goal of language comprehension. We present 2 studies of eye movements during real-time language processing, where the value of fixating on a social partner varies across different contexts. First, compared with children learning spoken English (n = 80), young American Sign Language (ASL) learners (n = 30) delayed gaze shifts away from a language source and produced a higher proportion of language-consistent eye movements. This result provides evidence that ASL learners adapt their gaze to effectively divide attention between language and referents, which both compete for processing via the visual channel. Second, English-speaking preschoolers (n = 39) and adults (n = 31) fixated longer on a speaker's face while processing language in a noisy auditory environment. Critically, like the ASL learners in Experiment 1, this delay resulted in gathering more visual information and a higher proportion of language-consistent gaze shifts. Taken together, these studies suggest that young listeners can adapt their gaze to seek visual information from social partners to support real-time language comprehension. (PsycInfo Database Record (c) 2020 APA, all rights reserved).