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Mobile app-based meditation is an effective self-care solution for depression, but limited evidence exists for the long-term benefits among autistic adults, who are at increased risk of experiencing depression. The primary goal of this study was to examine the feasibility and effectiveness of incorporating habit training into an app-based meditation intervention to maintain reductions in depressive symptoms among autistic adults. Participants were randomized to an App Only (who only received access to the meditation app), App + Habit Training (who received the meditation app and instructions for anchoring their app-based meditation to an existing routine), or a waitlist control group. All participants completed questionnaires at baseline, post-intervention, and 6 months post-intervention, and responded to SMS ecological momentary assessments regarding their meditation practice during the 8-week intervention and an 8-week follow-up period. The results show that the App + Habit Training group reported significantly more days with meditation per week during and after the intervention (p < 0.05) and also experienced a larger decrease in depression symptoms post-intervention and 6 months later (p < 0.05) relative to the control group. These findings demonstrate that app-based meditation habits are an effective self-care solution for autistic adults with depression, and anchoring is a promising strategy for establishing other healthy habits among autistic adults.

Access and usage of digital technologies is a marker of advantage in Australian schools. This study aims to identify how context impacts upon the enactment of the teaching and leading of the Digital Technologies Curriculum in schools labelled as disadvantaged. The study used a four-fold heuristic of contexts to analyse the work of educators in schools. The study found that external contexts structurally shape the teachers' agency with the Digital Technologies Curriculum. The study revealed that the enactment of the Digital Technologies Curriculum in disadvantaged contexts was enabled by additional supports and nuanced approaches. Successful enactment can occur when teacher and leader agency outperform the impact of structural disadvantage.

Focusing on teachers' practices amid a national curriculum 'implementation' project for schools identified as having high enrolments of students experiencing disadvantage, this paper uses narrative methods to illustrate what we refer to as teachers' everyday work-for-change. Teacher interview data was generated via a longitudinal multi-site case study. Two teachers at one school are selected for detailed attention because--despite their significant engagement, commitment, and work towards enacting the new curriculum--their innovations were not sustained. These cases provide a useful site of analysis of change as a practice, rather than a more common focus on change as an outcome. De Certeau's theory of everyday practice is used to discuss how work-for-change is an everyday feature of teacher practice in schools enrolling students experiencing disadvantage. This aspect of teachers' work in these settings is seldom acknowledged because successes are easily obscured by deficit discourses. Other factors contributing to the invisibility of teachers' work-for-change in these schools include the often-intangible nature of teachers' professional successes amid more formally visibilized failures, the ephemeral nature of everyday practice, and a workforce context characterised by teacher and leadership transience.

Abstract Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS.

Abstract Background Chronic obstructive pulmonary disease (COPD) is an inflammatory airway disease characterized by emphysema and chronic bronchitis and a leading cause of mortality worldwide. COPD is commonly associated with several comorbid diseases which contribute to exacerbated patient outcomes. Cigarette smoke (CS) is the most prominent risk factor for COPD development and progression and is known to be detrimental to numerous effector functions of lung resident immune cells, including phagocytosis and cytokine production. However, how CS mediates the various pathologies distant from the lung in COPD, and whether CS has a similar biological effect on systemic immune cells remains unknown. Methods C57BL/6 mice were exposed to 8 weeks of CS as an experimental model of COPD. Bone marrow cells were isolated from both CS-exposed and room air (RA) control mice and differentiated to bone marrow-derived macrophages (BMDMs). Airspace macrophages (AMs) were isolated from the same CS-exposed and RA mice and bulk RNA-Seq performed. The functional role of differentially expressed genes was assessed through gene ontology analyses. Ingenuity Pathway Analysis was used to determine the activation states of canonical pathways and upstream regulators enriched in differentially expressed genes in both cell types, and to compare the differences between the two cell types. Results CS induced transcriptomic changes in BMDMs, including an upregulation of genes in sirtuin signalling and oxidative phosphorylation pathways and a downregulation of genes involved in histone and lysine methylation. In contrast, CS induced decreased expression of genes involved in pathogen response, phagosome formation, and immune cell trafficking in AMs. Little overlap was observed in differentially expressed protein-coding genes in BMDMs compared to AMs and their associated pathways, highlighting the distinct effects of CS on immune cells in different compartments. Conclusions CS exposure can induce transcriptomic remodelling in BMDMs which is distinct to that of AMs. Our study highlights the ability of CS exposure to affect immune cell populations distal to the lung and warrants further investigation into the functional effects of these changes and the ensuing role in driving multimorbid disease.

Lipid II is an essential glycolipid found in bacteria. Accessing this valuable cell wall precursor is important both for studying cell wall synthesis and for studying/identifying novel antimicrobial compounds. Herein, we describe optimizations to the modular chemical synthesis of lipid II and unnatural analogues. In particular, the glycosylation step, a critical step in the formation of the central disaccharide unit (GlcNAc-MurNAc), was optimized. This was achieved by employing the use of glycosyl donors with diverse leaving groups. The key advantage of this approach lies in its adaptability, allowing for the generation of a wide array of analogues through the incorporation of alternative building blocks at different stages of synthesis.

The term “lovebirds” is often used to describe the loving behaviors and interactions between two romantic partners, but what specific processes distinguish these flourishing lovebird relationships from other committed but “numbed” relationships? The present study aimed to address this knowledge gap through the development and preliminary validation of the Lovebird Scale. The Lovebird Scale describes the thoughts, feelings, behaviors, and habits that constitute and maintain relationship flourishing, which in turn could promote aspects of individual flourishing such as positive affect. We conducted three studies using data collected from 996 English-speaking U.S. adults (64.2% Female, M = 39.2 years old) who reported being in a romantic relationship for at least six months (M = 11.2 years). In Study 1, we conducted an exploratory factor analysis to determine the underlying factor structure. In Study 2, confirmatory factor analyses revealed a three-factor model nested within a higher-order factor representing lovebird relationships. In Study 3, we cross-validated the higher-order structure, examined the construct validity of the scale, and explored associations between the Lovebird Scale and affective state. Finally, we discuss how the Lovebird Scale contributes to the growing field of positive relationship science as well as conceptual and clinical implications of the scale.

The introduction of the Literature strand within the Australian Curriculum requires all teachers to engage students in print and digital literature that embrace the cross-curriculum priorities and support students to examine, evaluate, and discuss literary texts. However, such curriculum change assumes that primary school teachers who have often not studied literature as a specific method, have the confidence and content and pedagogical knowledge to plan and implement programs. This paper investigates teachers' views of their level of confidence and preparedness to teach literature, and to explore teachers' practices, challenges and enablers in teaching literature in both print and digital environments. Results show that this group of 321 primary school teachers reported varying levels of confidence, knowledge and practices, and offers new insights into complex challenges they've experienced when interpreting and enacting the literature curriculum. Findings suggest the critical need for professional learning and discuss the implications for initial-teacher education programs.

Determining the layers of gene regulation within the innate immune response is critical to our understanding of the cellular responses to infection and dysregulation in disease. We identified a conserved mechanism of gene regulation in human and mouse via changes in alternative first exon (AFE) usage following inflammation, resulting in changes to the isoforms produced. Of these AFE events, we identified 95 unannotated transcription start sites in mice using a de novo transcriptome generated by long-read native RNA-sequencing, one of which is in the cytosolic receptor for dsDNA and known inflammatory inducible gene, Aim2. We show that this unannotated AFE isoform of Aim2 is the predominant isoform expressed during inflammation and contains an iron-responsive element in its 5'UTR enabling mRNA translation to be regulated by iron levels. This work highlights the importance of examining alternative isoform changes and translational regulation in the innate immune response and uncovers novel regulatory mechanisms of Aim2.

BACKGROUND: There is a lack of mechanism-driven, clinically relevant biomarkers in chronic obstructive pulmonary disease (COPD). Mitochondrial dysfunction, a proposed disease mechanism in COPD, is associated with the release of mitochondrial DNA (mtDNA), but plasma cell-free mtDNA has not been previously examined prospectively for associations with clinical COPD measures. METHODS: P-mtDNA, defined as copy number of mitochondrially-encoded NADH dehydrogenase-1 (MT-ND1) gene, was measured by real-time quantitative PCR in 700 plasma samples from participants enrolled in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Associations between p-mtDNA and clinical disease parameters were examined, adjusting for age, sex, smoking status, and for informative loss to follow-up. RESULTS: P-mtDNA levels were higher in participants with mild or moderate COPD, compared to smokers without airflow obstruction, and to participants with severe COPD. Baseline increased p-mtDNA levels were associated with better CAT scores in female smokers without airflow obstruction and female participants with mild or moderate COPD on 1-year follow-up, but worse 6MWD in females with severe COPD. Higher p-mtDNA levels were associated with better 6MWD in male participants with severe COPD. These associations were no longer significant after adjusting for informative loss to follow-up. CONCLUSION: In this study, p-mtDNA levels associated with baseline COPD status but not future changes in clinical COPD measures after accounting for informative loss to follow-up. To better characterize mitochondrial dysfunction as a potential COPD endotype, these results should be confirmed and validated in future studies. TRIAL REGISTRATION:  ClinicalTrials.gov NCT01969344 (SPIROMICS).

Paradoxes are particularly problematic in literacy as they often complicate learning. However, identifying and examining them can also tell us something about the inherent problems within social, political, and educational systems. This paper reports on an analysis of a total of 205 AJLL articles and editorials, published between 2011 and 2021. The purpose of the study was to identify the paradoxes associated with student language and literacy learning. The systematic literature review identified 311 instances of paradoxes across these 205 articles. Thirty instances of paradoxical terminology associated with student literacy learning were selected from the 311 instances. The excluded 271 instances of paradox were associated with policy contexts, teacher performance, and accountabilities, which are outside the scope of this article. The research in the 205 articles found that literacy learning was shaped by the skills of literacy learning, the complexity of student learning through standardised approaches, and textual plurality. The contexts of literacy learning spanned the virtual and real, the implications of national testing on local situations, and the changing nature of text and what it means to be literate. This review identified that students negotiate paradoxes associated with the risks of standardised testing, the narrowing of the writing curriculum, and understanding the variety of textual forms and practices. Identifying and examining these paradoxes will help address some of the persistent problems in literacy learning faced by students and teachers.

The scientific community has shown considerable interest in Industry 4.0 due to its capacity to revolutionise the manufacturing sector through digitalisation and data-driven decision-making. However, the actual implementation of Industry 4.0 within complex industrial settings presents obstacles that are typically beyond the scope of mainstream research articles. In this paper, a comprehensive case-study detailing our collaborative partnership with a leading medical device manufacturer is presented. The study traces its evolution from a state of limited digitalisation to the development of a digital intelligence platform that leverages data and machine learning models to enhance operations across a wide range of critical machines and assets. The main business objective was to enhance the energy efficiency of the manufacturing process, thereby improving its sustainability measures while also saving costs. The project encompasses energy modelling and analytics, Fault Detection and Diagnostics (FDD), renewable energy integration and advanced visualisation tools. Together, these components enable informed decision making in the context of energy efficiency.

Regional literature, specifically eye dialect, is conspicuously missing from language classrooms due to its non-normative orthography. Even native speakers of the language struggle with unconventional spellings as dictionaries become useless tools. Moreover, most readers lack intuition regarding regional speech phenomena or its orthographic representations. While we are all speakers of a dialect, many are only familiar with their regional variety. Salvadoran regional literature may feature “pue” instead of “pues”, “pos” in Mexican literature, and “po” in Chilean literature. All examples divert from the normative “pues” despite sharing the same contextual cues. In regional representations, “fue” is written as “jue” to convey the [ˈxwe] pronunciation of the word. These regional texts, like those written by Salvadoran author Salarrué, are extraordinarily interesting because they capture graphically the phonetic phenomena characteristic of languages in contact and/or dialectal variations such as elisions and aspirations, among others. In a study conducted by the researcher, it was found that heritage speakers of Spanish possess a unique background knowledge compared to native and non-native speakers. Along with linguistic decoding strategies, this proved to be beneficial for them when reading and understanding “Semos malos”. Heritage students (Group C) were able to ‘evaluate’ many types of ‘candidates’ and were well-equipped to understand global phonetic phenomena as portrayed in regional literature from other areas.

BackgroundTo assess the genetic architecture of hypertrophic cardiomyopathy (HCM) in patients of predominantly Chinese ancestry.MethodsWe sequenced HCM disease genes in Singaporean patients (n=224) and Singaporean controls (n=3634), compared findings with additional populations and White HCM cohorts (n=6179), and performed in vitro functional studies.ResultsSingaporean HCM patients had significantly fewer confidently interpreted HCM disease variants (pathogenic/likely pathogenic: 18%, P

Levels of iron and iron-related proteins including ferritin are higher in the lung tissue and lavage fluid of individuals with chronic obstructive pulmonary disease (COPD), when compared to healthy controls. Whether more iron in the extracellular milieu of the lung associates with distinct clinical phenotypes of COPD, including increased exacerbation susceptibility, is unknown. We measured iron and ferritin levels in the bronchoalveolar lavage fluid (BALF) of participants enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD (SPIROMICS) bronchoscopy sub-study (n = 195). BALF Iron parameters were compared to systemic markers of iron availability and tested for association with FEV1 % predicted and exacerbation frequency. Exacerbations were modelled using a zero-inflated negative binomial model using age, sex, smoking, and FEV1 % predicted as clinical covariates. BALF iron and ferritin were higher in participants with COPD and in smokers without COPD when compared to non-smoker control participants but did not correlate with systemic iron markers. BALF ferritin and iron were elevated in participants who had COPD exacerbations, with a 2-fold increase in BALF ferritin and iron conveying a 24% and 2-fold increase in exacerbation risk, respectively. Similar associations were not observed with plasma ferritin. Increased airway iron levels may be representative of a distinct pathobiological phenomenon that results in more frequent COPD exacerbation events, contributing to disease progression in these individuals.

Alveolar epithelial type II (AEC2) cells strictly regulate lipid metabolism to maintain surfactant synthesis. Loss of AEC2 cell function and surfactant production are implicated in the pathogenesis of the smoking-related lung disease chronic obstructive pulmonary disease (COPD). Whether smoking alters lipid synthesis in AEC2 cells and whether altering lipid metabolism in AEC2 cells contributes to COPD development are unclear. In this study, high-throughput lipidomic analysis revealed increased lipid biosynthesis in AEC2 cells isolated from mice chronically exposed to cigarette smoke (CS). Mice with a targeted deletion of the de novo lipogenesis enzyme, fatty acid synthase (FASN), in AEC2 cells (FasniΔAEC2) exposed to CS exhibited higher bronchoalveolar lavage fluid (BALF) neutrophils, higher BALF protein, and more severe airspace enlargement. FasniΔAEC2 mice exposed to CS had lower levels of key surfactant phospholipids but higher levels of BALF ether phospholipids, sphingomyelins, and polyunsaturated fatty acid–containing phospholipids, as well as increased BALF surface tension. FasniΔAEC2 mice exposed to CS also had higher levels of protective ferroptosis markers in the lung. These data suggest that AEC2 cell FASN modulates the response of the lung to smoke by regulating the composition of the surfactant phospholipidome.

IntroductionEmotional intelligence (EI) is associated with a range of positive health, wellbeing, and behavioral outcomes. The present article describes the development and validation of an online training program for increasing EI abilities in adults. The training program was based on theoretical models of emotional functioning and empirical literature on successful approaches for training socioemotional skills and resilience.MethodsAfter an initial design, programming, and refinement process, the completed online program was tested for efficacy in a sample of 326 participants (72% female) from the general population. Participants were randomly assigned to complete either the EI training program (n = 168) or a matched placebo control training program (n = 158). Each program involved 10-12 hours of engaging online content and was completed during either a 1-week (n = 175) or 3-week (n = 151) period.ResultsParticipants who completed the EI training program showed increased scores from pre- to post-training on standard self-report (i.e., trait) measures of EI (relative to placebo), indicating self-perceived improvements in recognizing emotions, understanding emotions, and managing the emotions of others. Moreover, those in the EI training also showed increased scores in standard performance-based (i.e., ability) EI measures, demonstrating an increased ability to strategically use and manage emotions relative to placebo. Improvements to performance measures also remained significantly higher than baseline when measured six months after completing the training. The training was also well-received and described as helpful and engaging.DiscussionFollowing a rigorous iterative development process, we created a comprehensive and empirically based online training program that is well-received and engaging. The program reliably improves both trait and ability EI outcomes and gains are sustained up to six months post-training. This program could provide an easy and scalable method for building emotional intelligence in a variety of settings.

BackgroundChronic (ie, long-term) elevated stress is associated with a number of mental and physical health conditions. Mindfulness meditation mobile apps are a promising tool for stress self-management that can overcome several barriers associated with in-person interventions; however, to date, poor app-based intervention adherence has limited the efficacy of these mobile health tools. Anchoring, or pairing, a new behavior with an existing routine has been shown to effectively establish habits that are maintained over time, but this strategy typically only works for those with high initial motivation and has yet to be tested for maintaining meditation with a mobile app. ObjectiveThis study will test novel combinations of behavioral economics–based incentives with the anchoring strategy for establishing and maintaining adherence to an effective dose of meditation with a mobile app. MethodsThis 16-week study will use a 5-arm, parallel, partially blinded (participants only), randomized controlled design. We will implement a fractional factorial study design that varies the use of self-monitoring messages and financial incentives to support participants’ use of their personalized anchoring strategy for maintaining adherence to a ≥10 minute-per-day meditation prescription during an 8-week intervention period, followed by an 8-week postintervention observation period. Specifically, we will vary the use of self-monitoring messages of either the target behavior (ie, meditation tracking) or the outcome associated with the target behavior (ie, mood symptom tracking). We will also vary the use of financial incentives conditional on either meditation at any time of day or meditation performed at approximately the same time of day as participants’ personalized anchors. ResultsContinuous meditation app use data will be used to measure weekly meditation adherence over the 16-week study period as a binary variable equal to 1 if participants complete ≥10 minutes of meditation for ≥4 days per week and 0 otherwise. We will measure weekly anchoring plan adherence as a binary variable equal to 1 if participants complete ≥10 minutes of meditation within +1 or −1 hour of the timing of their chosen anchor on ≥4 days per week and 0 otherwise. In addition to these primary measures of meditation and anchoring plan adherence, we will also assess the secondary measures of stress, anxiety, posttraumatic stress disorder, sleep disturbance, and meditation app habit strength at baseline, week 8, and week 16. ConclusionsThis study will fill an important gap in the mobile health literature by testing novel intervention approaches for establishing and maintaining adherence to app-based mindfulness meditation. If successful, this study will identify an accessible and scalable stress self-management intervention that can help combat stress in the United States. Trial RegistrationClinicalTrials.gov NCT05217602; https://clinicaltrials.gov/ct2/show/NCT05217602 International Registered Report Identifier (IRRID)DERR1-10.2196/39930

In this review, the Basic and Translational Science Assembly of the European Respiratory Society provides an overview of the 2022 International Congress highlights. We discuss the consequences of respiratory events from birth until old age regarding climate change related alterations in air quality due to pollution caused by increased ozone, pollen, wildfires and fuel combustion as well as the increasing presence of microplastic and microfibres. Early life events such as the effect of hyperoxia in the context of bronchopulmonary dysplasia and crucial effects of the intrauterine environment in the context of pre-eclampsia were discussed. The Human Lung Cell Atlas (HLCA) was put forward as a new point of reference for healthy human lungs. The combination of single-cell RNA sequencing and spatial data in the HLCA has enabled the discovery of new cell types/states and niches, and served as a platform that facilitates further investigation of mechanistic perturbations. The role of cell death modalities in regulating the onset and progression of chronic lung diseases and its potential as a therapeutic target was also discussed. Translational studies identified novel therapeutic targets and immunoregulatory mechanisms in asthma. Lastly, it was highlighted that the choice of regenerative therapy depends on disease severity, ranging from transplantation to cell therapies and regenerative pharmacology.

This article provides a selective overview of the novel in 2023. In addition, through references to the technical and editorial changes currently affecting Livres Hebdo, France's leading book publishing trade journal, the essay considers ways in which the increasing emphasis given to online publishing is influencing the development of the contemporary business of literature. [ABSTRACT FROM AUTHOR]

Imperatives to connect the worlds of home and school, evident in global policies of family engagement and partnership initiatives between teachers and parents to support children's education are viewed as key dimensions of academic success. However, developing ways to meaningfully connect and engage teachers, parents and students in learning ecologies remains elusive, contested and increasingly complex in the digital age. Teachers are encouraged to draw on their students' digital 'funds of knowledge' to create innovative learning opportunities and develop capacities for creativity and critical thinking. Despite significant research into creativity pedagogies and the inclusion of parents in policy documents urging for increased innovation in schooling, which often implies the use of digital technologies, parents are largely invisible in research into creative pedagogies. The data explored in this article are drawn from a larger project which adopted a teacher-as-inquirer approach to investigate teacher, student and parent experiences and understandings of innovative teaching designed to integrate creative and critical thinking with digital literacy practices. The analysis mobilises the key features of creative and innovative learning environments identified in the research literature to explore teachers' initiatives to develop reflexive and innovative pedagogies and foregrounds the ways in which incorporation of digital media impacted on parental engagement in their children's learning. Findings highlight significant challenges for schools and teachers to meaningfully and sustainably connect home and school learning which positions children, teachers and parents as agentic and creative.

As mobile and connected digital practices reshape social, interpersonal and learning relationships, it is increasingly challenging for teachers and schools to keep pace with rapid change. This paper reports on a professional learning project which set out to support teachers to learn more about how students in their classes used technologies, which technologies they used, what they thought about how they and others used them, and what they used them for. Teachers' research into students' digital use acted as a necessary intervention and prior step to developing classroom- and school-level responses to young people's use of digital technologies. The paper reports on teachers' findings, their responses to what they learnt and the implications for schools. In parallel, it reports also on the processes of the research and its deliverables as a professional learning enterprise, and the operation and value of this approach as professional learning methodology.

Contemporary students, accustomed to the agency and multimodality afforded by digital media in their out-of-school lives, require literature pedagogies that provide currency and appeal while furthering their understandings of literary techniques. Literature circles have long promoted student voice and choice but can lack criticality and attention to literary devices and fail to capitalize on the potential of digital technologies. The authors explore literature circle pedagogies designed to develop knowledge of literary theme and mood, highlighting multimodal responses foregrounding students' identities. Two analytical lenses, curation and multimodality, underpin this investigation into the opportunities presented through pedagogical design. Curation, an expanded concept of text creation, is used to analyze opportunities for student displays of literary knowledge and identity through multimodal resources. Multimodal resources are understood as combinations of modes of meaning. Together, these analytical lenses offer insight into ways in which multimodal curation pedagogies enable students' development of literary knowledge.

Early millennial arguments tended to regard young people's out of school literacies with enthusiasm, with school print literacies by comparison seen as lacking currency. More recent critiques of such binary positioning of home-school digital practices instead recommend seeking connections and continuities. However, with teachers rarely gaining direct access to knowledge of students' out of school digital lives, they are often left to speculate about the actuality of their students' everyday digital practices. In line with recent directions in Australian educational policy, this paper draws on evidence from a project in which literacy teachers were positioned as researchers of their students' everyday digital practices. It explores how teachers designed and conducted research into their students' everyday digital funds of knowledge and associated pedagogical renewal. Teacher research was embedded in and iteratively informed pedagogy. Teachers sought to position students as active research participants with opportunities to influence classroom pedagogies. The effects of teacher research on pedagogy are analysed, specifically pedagogies which positioned students agentically. The new literacies concept of curation, an expanded notion of authorship, is used as an analytical tool to consider to what extent agentic positioning allowed students to curate the incorporation of digital media and digital literacy practices into classroom programs.

We report the discovery of COOL J0335−1927, a quasar at z = 3.27 lensed into three images with a maximum separation of 23.″3 by a galaxy cluster at z = 0.4178. To date, this is the highest redshift wide-separation lensed quasar known. In addition, COOL J0335−1927 shows several strong intervening absorbers visible in the spectra of all three quasar images with varying equivalent widths. The quasar also shows mini-broad line absorption. We construct a parametric strong gravitational lens model using ground-based imaging, constrained by the redshift and positions of the quasar images as well as the positions of three other multiply imaged background galaxies. Using our best-fit lens model, we calculate the predicted time delays between the three quasar images to be Δ t _AB = ${499}_{-146}^{+141}$ (stat) and Δ t _AC = $-{127}_{-17}^{+83}$ (stat) days. Folding in systematic uncertainties, the model-predicted time delays are within the ranges 240 < Δ t _AB < 700 and −300 < Δ t _AC < −30. We also present g -band photometry from archival Dark Energy Camera Legacy Survey and Pan-STARRS imaging, and new multi-epoch observations obtained between 2022 September 18 UT and 2023 February 22 UT, which demonstrate significant variability in the quasar and will eventually enable the measurement of the time delay between the three quasar images. The currently available light curves are consistent with the model-predicted time delays. This is the fifth paper from the COOL-LAMPS collaboration.

Copper depletion has been reported to improve survival in patients with triple negative breast cancer (TNBC) but the underlying mechanisms are not completely understood. Here, the authors show that copper chelation reduces mitochondrial oxidative phosphorylation leading to decreased TNBC metastasis.

Nikolaos Serifis,1 Diamantis I Tsilimigras,2 Daniel J Cloonan,3 Timothy M Pawlik2 1Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, USA; 2Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA; 3Department of Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USACorrespondence: Diamantis I TsilimigrasDepartment of Surgery, The Ohio State University, Wexner Medical Center, 410 W 10th Avenue, Columbus, OH, 43210, USATel +1 215 987 9177Email diamantis.tsilimigras@osumc.eduAbstract: Intrahepatic cholangiocarcinoma (ICC) is one of the rarest and most aggressive types of cancer. The symptoms of ICC patients can be vague, leading to late diagnosis and dismal prognosis. In this review, we investigated the treatment options for ICC, as well as ways to overcome challenges in identifying and treating this disease. Imaging remains the gold standard to diagnose ICC. Patients are staged based on the tumor, nodes and metastases (TNM) staging system. Patients eligible for surgical resection should undergo surgery with curative intent with the goal of microscopically disease-free margins (R0 resection) along with lymphadenectomy. Minimal invasive surgery (MIS) and liver transplantation have recently been offered as possible ways to improve disease outcomes. ICC recurrence is relatively common and, thus, most patients will need to be treated with systemic therapy. Several clinical trials have recently investigated the use of neoadjuvant (NT) and adjuvant therapies for ICC. NT may offer an opportunity to downsize larger tumors and provide patients, initially ineligible for surgery, with an opportunity for resection. NT may also treat occult micro-metastatic disease, as well as define tumor biology prior to surgical resection, thereby decreasing the risk for early postoperative recurrence. Adjuvant systemic therapy may improve outcomes of patients with ICC following surgery. Ongoing clinical trials are investigating new targeted therapies that hold the hope of improving long-term outcomes of patients with ICC.Keywords: liver, intrahepatic cholangiocarcinoma, resection, outcomes

Iron is a key element for systemic oxygen delivery and cellular energy metabolism. Thus regulation of systemic and local iron metabolism is key for maintaining energy homeostasis. Significant changes in iron levels due to malnutrition or hemorrhage, have been associated with several diseases such as hemochromatosis, liver cirrhosis and COPD. Macrophages are key cells in regulating iron levels in tissues as they sequester excess iron. How iron overload affects macrophage differentiation and function remains a subject of debate. Here we used an in vitro model of monocyte-to-macrophage differentiation to study the effect of iron overload on macrophage function. We found that providing excess iron as soluble ferric ammonium citrate (FAC) rather than as heme-iron complexes derived from stressed red blood cells (sRBC) interferes with macrophage differentiation and phagocytosis. Impaired macrophage differentiation coincided with increased expression of oxidative stress-related genes. Addition of FAC also led to increased levels of cellular and mitochondrial reactive oxygen species (ROS) and interfered with mitochondrial function and ATP generation. The effects of iron overload were reproduced by the mitochondrial ROS-inducer rotenone while treatment with the ROS-scavenger N-Acetylcysteine partially reversed FAC-induced effects. Finally, we found that iron-induced oxidative stress interfered with upregulation of M-CSFR and MAFB, two crucial determinants of macrophage differentiation and function. In summary, our findings suggest that high levels of non-heme iron interfere with macrophage differentiation by inducing mitochondrial oxidative stress. These findings might be important to consider in the context of diseases like chronic obstructive pulmonary disease (COPD) where both iron overload and defective macrophage function have been suggested to play a role in disease pathogenesis.

There is growing evidence in the literature suggesting that caste differentiation in the stingless bee, Melipona scutellaris, and other bees in the genus Melipona, is triggered by environmental signals, particularly a primer pheromone. With the proper amount of food and a chemical stimulus, 25% of females emerge as queens, in agreement with a long-standing "two loci/two alleles model" proposed in the 1950s. We surmised that these larvae must be equipped with an olfactory system for reception of these chemical signals. Here we describe for the first time the diversity of antennal sensilla in adults and the morphology of larvae of M. scutellaris. Having found evidence for putative olfactory sensilla in larvae, we next asked whether olfactory proteins were expressed in larvae. Since the molecular basis of M. scutellaris is still unknown, we cloned olfactory genes encoding chemosensory proteins (CSP) and odorant-binding proteins (OBPs) using M. scutellaris cDNA template and primers designed on the basis CSPs and OBPs previously reported from the European honeybee, Apis mellifera. We cloned two CSP and two OBP genes and then attempted to express the proteins encoded by these genes. With a recombinant OBP, MscuOBP8, and a combinatorial single-chain variable fragment antibody library, we generated anti-MscuOBP8 monoclonal antibody. By immunohistochemistry we demonstrated that the anti-MscuOBP8 binds specifically to the MscuOBP8. Next, we found evidence that MscuOBP8 is expressed in M. scutellaris larvae and it is located in the mandibular region, thus further supporting the hypothesis of olfactory function in immature stages. Lastly, molecular modeling suggests that MscuOBP8 may function as a carrier of primer pheromones or other ligands.

There is growing evidence in the literature suggesting that caste differentiation in the stingless bee, Melipona scutellaris, and other bees in the genus Melipona, is triggered by environmental signals, particularly a primer pheromone. With the proper amount of food and a chemical stimulus, 25% of females emerge as queens, in agreement with a long-standing "two loci/two alleles model" proposed in the 1950s. We surmised that these larvae must be equipped with an olfactory system for reception of these chemical signals. Here we describe for the first time the diversity of antennal sensilla in adults and the morphology of larvae of M. scutellaris. Having found evidence for putative olfactory sensilla in larvae, we next asked whether olfactory proteins were expressed in larvae. Since the molecular basis of M. scutellaris is still unknown, we cloned olfactory genes encoding chemosensory proteins (CSP) and odorant-binding proteins (OBPs) using M. scutellaris cDNA template and primers designed on the basis CSPs and OBPs previously reported from the European honeybee, Apis mellifera. We cloned two CSP and two OBP genes and then attempted to express the proteins encoded by these genes. With a recombinant OBP, MscuOBP8, and a combinatorial single-chain variable fragment antibody library, we generated anti-MscuOBP8 monoclonal antibody. By immunohistochemistry we demonstrated that the anti-MscuOBP8 binds specifically to the MscuOBP8. Next, we found evidence that MscuOBP8 is expressed in M. scutellaris larvae and it is located in the mandibular region, thus further supporting the hypothesis of olfactory function in immature stages. Lastly, molecular modeling suggests that MscuOBP8 may function as a carrier of primer pheromones or other ligands.

Abstract Background There is a lack of mechanism-driven, clinically relevant biomarkers in chronic obstructive pulmonary disease (COPD). Mitochondrial dysfunction, a proposed disease mechanism in COPD, is associated with the release of mitochondrial DNA (mtDNA), but plasma cell-free mtDNA has not been previously examined prospectively for associations with clinical COPD measures. Methods P-mtDNA, defined as copy number of mitochondrially-encoded NADH dehydrogenase-1 (MT-ND1) gene, was measured by real-time quantitative PCR in 700 plasma samples from participants enrolled in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Associations between p-mtDNA and clinical disease parameters were examined, adjusting for age, sex, smoking status, and for informative loss to follow-up. Results P-mtDNA levels were higher in participants with mild or moderate COPD, compared to smokers without airflow obstruction, and to participants with severe COPD. Baseline increased p-mtDNA levels were associated with better CAT scores in female smokers without airflow obstruction and female participants with mild or moderate COPD on 1-year follow-up, but worse 6MWD in females with severe COPD. Higher p-mtDNA levels were associated with better 6MWD in male participants with severe COPD. These associations were no longer significant after adjusting for informative loss to follow-up. Conclusion In this study, p-mtDNA levels associated with baseline COPD status but not future changes in clinical COPD measures after accounting for informative loss to follow-up. To better characterize mitochondrial dysfunction as a potential COPD endotype, these results should be confirmed and validated in future studies. Trial Registration: ClinicalTrials.gov NCT01969344 (SPIROMICS)

Abstract Nutritional immunity is the sequestration of bioavailable trace metals such as iron, zinc and copper by the host to limit pathogenicity by invading microorganisms. As one of the most conserved activities of the innate immune system, limiting the availability of free trace metals by cells of the immune system serves not only to conceal these vital nutrients from invading bacteria but also operates to tightly regulate host immune cell responses and function. In the setting of chronic lung disease, the regulation of trace metals by the host is often disrupted, leading to the altered availability of these nutrients to commensal and invading opportunistic pathogenic microbes. Similarly, alterations in the uptake, secretion, turnover and redox activity of these vitally important metals has significant repercussions for immune cell function including the response to and resolution of infection. This review will discuss the intricate role of nutritional immunity in host immune cells of the lung and how changes in this fundamental process as a result of chronic lung disease may alter the airway microbiome, disease progression and the response to infection.