Fungal melanin suppresses airway epithelial chemokine secretion through blockade of calcium fluxing.

Respiratory infections caused by the human fungal pathogen Aspergillus fumigatus are a major cause of mortality for immunocompromised patients. Exposure to these pathogens occurs through inhalation, although the role of the respiratory epithelium in disease pathogenesis has not been fully defined. Employing a primary human airway epithelial model, we demonstrate that fungal melanins potently block the post-translational secretion of the chemokines CXCL1 and CXCL8 independent of transcription or the requirement of melanin to be phagocytosed, leading to a significant reduction in neutrophil recruitment to the apical airway both in vitro and in vivo. Aspergillus-derived melanin, a major constituent of the fungal cell wall, dampened airway epithelial chemokine secretion in response to fungi, bacteria, and exogenous cytokines. Furthermore, melanin muted pathogen-mediated calcium fluxing and hindered actin filamentation. Taken together, our results reveal a critical role for melanin interaction with airway epithelium in shaping the host response to fungal and bacterial pathogens.

Botensilimab, an Fc-enhanced anti-CTLA-4 antibody, is effective against tumors poorly responsive to conventional immunotherapy.

Conventional immune checkpoint inhibitors (ICI) targeting CTLA-4 elicit durable survival, but primarily in patients with immune-inflamed tumors. Although the mechanisms underlying response to anti-CTLA-4 remain poorly understood, Fc-gamma receptor (FcγR) IIIA co-engagement appears critical for activity, potentially explaining the modest clinical benefits of approved anti-CTLA-4 antibodies. We demonstrate that anti-CTLA-4 engineered for enhanced FcγR affinity leverages FcγR-dependent mechanisms to potentiate T cell responsiveness, reduce intratumoral Tregs, and enhance antigen presenting cell activation. Fc-enhanced anti-CTLA-4 promoted superior efficacy in mouse models and remodeled innate and adaptive immunity versus conventional anti-CTLA-4. These findings extend to patients treated with botensilimab, an Fc-enhanced anti-CTLA-4 antibody, with clinical activity across multiple poorly immunogenic and ICI treatment-refractory cancers. Efficacy was independent of tumor neoantigen burden or FcγRIIIA genotype. However, FcγRIIA and FcγRIIIA expression emerged as potential response biomarkers. These data highlight the therapeutic potential of Fc-enhanced anti-CTLA-4 antibodies in cancers unresponsive to conventional ICI therapy.

'It Is Good to See the Person As a Whole Person and Continue to Improve Our Psychologically Informed Working': A Thematic Analysis of Clinical Psychology Trainee Placements in Homelessness Settings.

OBJECTIVES: The National Framework for Inclusion Health identified the need for collaborative action between the NHS and third sector health to improve access and outcomes for Inclusion Health groups. Clinical psychology trainee placements in homelessness settings could be a valuable pathway to improving access to psychological support for people experiencing homelessness and the provision of clinical services, which is key to developing the workforce and a catalyst for the future recruitment of clinical psychologists in the third sector. METHODS: A qualitative evaluation was conducted using semistructured interviews to explore the perspectives of clinical psychology trainees, supervisors, staff in homelessness settings and a peer mentor. Twenty-two participants were recruited from two universities and six services across the South East, including 11 clinical psychology trainees, six supervisors, four placement staff and one peer mentor. RESULTS: Placement staff described the value of a psychological approach but identified some challenges to be overcome. Induction was identified as the key to success. Supervisors recognised the breadth and depth added to trainees' knowledge and skills alongside significant challenges. Trainees valued the opportunities to work in homelessness settings and develop their understanding of the role. The peer mentor identified collaborative working as especially important. CONCLUSIONS: Clinical psychology trainee placements are a necessary programme to fulfil the NHS vision for Inclusion Health. These placements equip the health and social care workforce to create excellent and sustainable provisions to improve the physical and mental health of people experiencing homelessness whilst also providing much-needed psychological support for staff. PATIENT AND PUBLIC CONTRIBUTION: Psychologically Informed Environments Through Staff Training: Staff training and support within these placements contribute to the development of psychologically informed environments. This not only leads to better outcomes for both staff and clients but also aligns with the objectives of the National Framework for Inclusion Health, fostering sustainable provision for the health needs of people experiencing homelessness (PEH). Enhanced Therapeutic Adaptability: Trainees gain invaluable experience in adapting therapy to meet the diverse needs of clients, benefiting both trainees and clients alike. This adaptability fosters more effective therapeutic relationships and contributes to the improvement of inclusion health provision in the long term. Tailored Therapy for Timely Intervention: Clinical psychology trainee placements in homelessness settings offer therapy that bypasses long waiting times for interventions, crucial for individuals experiencing homelessness. This flexible approach caters to the unpredictable engagement levels of PEH, ensuring timely support aligning with the Health and Care Act 2022 to improve overall health and address health disparities through primary care networks.

Host innate immune systems gather intel on invading microbes via pathogen-derived extracellular vesicles.

Extracellular vesicles (EVs) are membrane-bound vesicles released into the extracellular milieu from various cell types including host cells and pathogens that infect them. As carriers of nucleic acids, proteins, lipids, metabolites, and virulence factors, EVs act as delivery vehicles for intercellular communication and quorum sensing. Innate immune cells have the capacity to intercept, internalize, and interpret 'messages' contained within these EVs. This review categorizes the ability of EVs secreted by bacterial, parasitic, and fungal pathogens to trigger both pro- and anti-inflammatory innate immune responses in the host. Understanding molecular pathways and inflammatory responses activated in innate immune cells upon pathogen-derived EV stimulation is critical to gain insight into potential therapeutics and combat these infectious diseases.

BTK inhibitor-induced defects in human neutrophil effector activity against Aspergillus fumigatus are restored by TNF-α.

Inhibition of Bruton's tyrosine kinase (BTK) through covalent modifications of its active site (e.g., ibrutinib [IBT]) is a preferred treatment for multiple B cell malignancies. However, IBT-treated patients are more susceptible to invasive fungal infections, although the mechanism is poorly understood. Neutrophils are the primary line of defense against these infections; therefore, we examined the effect of IBT on primary human neutrophil effector activity against Aspergillus fumigatus. IBT significantly impaired the ability of neutrophils to kill A. fumigatus and potently inhibited reactive oxygen species (ROS) production, chemotaxis, and phagocytosis. Importantly, exogenous TNF-α fully compensated for defects imposed by IBT and newer-generation BTK inhibitors and restored the ability of neutrophils to contain A. fumigatus hyphal growth. Blocking TNF-α did not affect ROS production in healthy neutrophils but prevented exogenous TNF-α from rescuing the phenotype of IBT-treated neutrophils. The restorative capacity of TNF-α was independent of transcription. Moreover, the addition of TNF-α immediately rescued ROS production in IBT-treated neutrophils, indicating that TNF-α worked through a BTK-independent signaling pathway. Finally, TNF-α restored effector activity of primary neutrophils from patients on IBT therapy. Altogether, our data indicate that TNF-α rescued the antifungal immunity block imposed by inhibition of BTK in primary human neutrophils.

The effectiveness of pharmacological and lifestyle interventions to reduce the risk of diabetes and hyperglycaemia following gestational diabetes: A systematic review and meta-analysis.

AIMS: To synthesize the available evidence to better understand the effectiveness of interventions to prevent or delay hyperglycaemia and Type 2 diabetes mellitus (T2DM) postnatally in women with current or previous gestational diabetes mellitus (GDM). METHODS: We searched five databases up to December 2020 for primary peer-reviewed articles reporting postpartum glycaemic outcomes in women with (previous) GDM following pharmacological or lifestyle intervention. Outcomes were relative risk of T2DM or continuous measures of glycaemia, change or at follow-up. A minimum of two studies evaluating the same intervention-outcome combination were needed to conduct meta-analyses, otherwise studies were described narratively. Meta-regression was used to evaluate whether associations varied by additional variables. We assessed risk of bias using the Critical Appraisal Skills Programme checklist. PROSPERO record CRD42018102380. RESULTS: We included 31 studies in the review with a total sample size of 8624 participants, and 26 studies in meta-analyses. Two-thirds of studies followed up participants at 1 year or less. Pharmacological interventions were associated with reduced risk of T2DM (0.80 [95% CI 0.64-1.00], n = 6 studies), as were lifestyle interventions albeit with a smaller effect size (0.88 [95% CI 0.76-1.01], n = 12 studies). Dietary and physical activity interventions were associated with a small reduction in fasting plasma glucose, particularly in longer interventions, but inconsistent effects were seen for other continuous outcomes. CONCLUSIONS: Although possibly due to chance, interventions to reduce hyperglycaemia after GDM may be effective. Future research should improve understanding of how interventions affect glucose control and how to optimise interventions for this population.

Point-of-Care Ultrasound for High-Risk Pregnancy Screening in Rural Nepal.

By training nurses and midwives on the basics of obstetric ultrasound, high-risk pregnancies in remote Nepalese villages can be identified and triaged. American radiology residents traveling to Nepal can improve their real-time, hands-on ultrasound scanning skills while learning the intricacies of practicing medicine in a low- and middle-income country. Global outreach work is increasing in popularity among US radiologists, emphasizing the importance of training radiology residents in point-of-care ultrasound.

Lewy body dementia: Overcoming barriers and identifying solutions.

Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public-health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public-domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating therapeutic development and improving patient care. This white paper outlines the opportunities for bridging the major LBD gaps and creates the framework for collaboration in that endeavor. HIGHLIGHTS: A group representing academia, government, industry, and consulting expertise was convened to discuss current progress in Dementia with Lewy Body care and research. Consideration of expert opinion,natural language processing of the literature as well as publicly available data bases, and Delphi inspired discussion led to a proposed consensus document of priorities for the field.

Candida albicans extracellular vesicles trigger type I IFN signalling via cGAS and STING.

The host type I interferon (IFN) pathway is a major signature of inflammation induced by the human fungal pathogen, Candida albicans. However, the molecular mechanism for activating this pathway in the host defence against C. albicans remains unknown. Here we reveal that mice lacking cyclic GMP-AMP synthase (cGAS)-stimulator of IFN genes (STING) pathway components had improved survival following an intravenous challenge by C. albicans. Biofilm-associated C. albicans DNA packaged in extracellular vesicles triggers the cGAS-STING pathway as determined by induction of interferon-stimulated genes, IFNß production, and phosphorylation of IFN regulatory factor 3 and TANK-binding kinase 1. Extracellular vesicle-induced activation of type I IFNs was independent of the Dectin-1/Card9 pathway and did not require toll-like receptor 9. Single nucleotide polymorphisms in cGAS and STING potently altered inflammatory cytokine production in human monocytes challenged by C. albicans. These studies provide insights into the early innate immune response induced by a clinically significant fungal pathogen.

Correction: Spatial variation and antecedent sea surface temperature conditions influence Hawaiian intertidal community structure.

[This corrects the article DOI: 10.1371/journal.pone.0286136.].

Predicting language outcomes in bilingual children with Down syndrome.

Continuous approaches to measuring bilingualism have recently emerged as a means of understanding individual variation in language abilities. To date, limited information is available to assist in understanding the language abilities of bilingual children with Down syndrome (DS), who are specifically known to have a large variation in linguistic outcomes. Group studies in this population report that children exposed to two languages do not differ from their monolingual counterparts after considering age and non-verbal cognitive abilities, although no study to date has examined the relationship between the amount of exposure to one language and the linguistic abilities in the other language within this population. This study sought to identify whether exposure to an additional language, specifically Welsh, predicted linguistic abilities in the majority language, in this case, English. Sixty-five children between the ages of 5;5-16;9 who had varied linguistic experiences completed a range of cognitive and linguistic assessments. Results from hierarchical regression analyses show that the amount of exposure to Welsh had no impact on language abilities in English, after controlling for non-verbal cognitive abilities, short-term memory and socioeconomic status. This demonstrates that exposure to an additional language does not have a negative impact on language development, a finding that has important clinical and educational implications.

Spatial variation and antecedent sea surface temperature conditions influence Hawaiian intertidal community structure.

Global sea surface temperatures (SSTs) are increasing, and in Hawai'i, rates of ocean warming are projected to double by the end of the 21st century. However, current nearshore warming trends and their possible impacts on intertidal communities are not well understood. This study represents the first investigation into the possible effects of rising SST on intertidal algal and invertebrate communities across the Main Hawaiian Islands (MHI). By utilizing citizen-science data coupled with high-resolution, daily SST satellite measurements from 12 intertidal sites across the MHI from 2004-2019, the response of intertidal algal and invertebrate abundance and community diversity to changes in SST was investigated across multiple spatial scales. Results show high rates of SST warming (0.40°C Decade-1) over this study's timeframe, similar to predicted rates of warming for Hawai'i by the end of the 21st century. Changes in abundance and diversity in response to SST were variable among intertidal sites, but differences in antecedent SST among intertidal sites were significantly associated with community dissimilarity. In addition, a statistically significant positive relationship was found between SST and Simpson's diversity index, and a significant relationship was also found between SST and the abundance of six dominant taxa. For five of these six dominant taxa, antecedent SSTs over the 6-12 months preceding sampling were the most influential for describing changes to abundance. The increase in community diversity in response to higher SSTs was best explained by temperatures in the 10 months preceding sampling, and the resultant decreased abundance of dominant turf algae. These results highlight rapidly warming nearshore SSTs in Hawai'i and the longer-term effects of antecedent SSTs as significant drivers of change within Hawaiian intertidal communities. Therefore, we suggest that future research and management should consider the possibility of lagging effects of antecedent SST on intertidal communities in Hawai'i and elsewhere.

Other Novel PET Radiotracers for Breast Cancer.

Many novel PET radiotracers have demonstrated potential use in breast cancer. Although not currently approved for clinical use in the breast cancer population, these innovative imaging agents may one day play a role in the diagnosis, staging, management, and even treatment of breast cancer.

Food Insecurity, Food Assistance, and Psychological Distress among University Students: Cross-Sectional Survey Western Australia, 2020.

University students have been identified as a population sub-group vulnerable to food insecurity. This vulnerability increased in 2020 due to the COVID-19 pandemic. This study aimed to assess factors associated with food insecurity among university students and the differences between students with and without children. A cross-sectional survey of (n = 213) students attending one university in Western Australia measured food insecurity, psychological distress, and socio-demographic characteristics. Logistic regression analyses were conducted to identify factors associated with food insecurity. Forty-eight percent of students who responded to the survey had experienced food insecurity in 2020. International students who were studying in Australia were nine times more likely to experience food insecurity than domestic students (AOR = 9.13; 95% CI = 2.32-35.97). International students with children were more likely to experience food insecurity than international students without children (p < 0.001) and domestic students with (p < 0.001) or without children (p < 0.001). For each unit increase in depression level, the likelihood of experiencing food insecurity increased (AOR = 1.62; 95% CI = 1.12-2.33). Findings show a higher prevalence of food insecurity among international university students and students with children during the COVID-19 pandemic and that food insecurity was associated with higher levels of psychological distress. These findings highlight the need for targeted interventions to mitigate the risk of food insecurity among Australian university students, particularly among international students, students with children, and those experiencing psychological distress.

Cross-kingdom anti-inflammatory effects of fungal melanin on airway epithelium by post-translational blockade of chemokine secretion.

Respiratory infections caused by the human fungal pathogens, Aspergillus fumigatus and Cryptococcus neoformans, are a major cause of mortality for immunocompromised patients. Exposure to these pathogens occurs through inhalation, although the role of the respiratory epithelium in disease pathogenesis has not been defined. Employing a primary human airway epithelial model, we demonstrate that fungal melanins potently block the post-translational secretion of CXCL1 and CXCL8 independent of transcription or the requirement of melanin to be phagocytosed, leading to a significant reduction of neutrophils to the apical airway both in vitro and in vivo. Aspergillus-derived melanin, a major constituent of the fungal cell wall, has far-reaching effects, dampening airway epithelial chemokine production in response to fungi, bacteria, and exogenous cytokines. Taken together, our results reveal a critical role for melanin interaction with airway epithelium in shaping the host response to fungal and bacterial pathogens.

The C-Type Lectin Receptor Dectin-2 Is a Receptor for Aspergillus fumigatus Galactomannan.

Aspergillus fumigatus is a ubiquitous environmental mold that causes significant mortality particularly among immunocompromised patients. The detection of the Aspergillus-derived carbohydrate galactomannan in patient serum and bronchoalveolar lavage fluid is the major biomarker used to detect A. fumigatus infection in clinical medicine. Despite the clinical relevance of this carbohydrate, we lack a fundamental understanding of how galactomannan is recognized by the immune system and its consequences. Galactomannan is composed of a linear mannan backbone with galactofuranose sidechains and is found both attached to the cell surface of Aspergillus and as a soluble carbohydrate in the extracellular milieu. In this study, we utilized fungal-like particles composed of highly purified Aspergillus galactomannan to identify a C-type lectin host receptor for this fungal carbohydrate. We identified a novel and specific interaction between Aspergillus galactomannan and the C-type lectin receptor Dectin-2. We demonstrate that galactomannan bound to Dectin-2 and induced Dectin-2-dependent signaling, including activation of spleen tyrosine kinase, gene transcription, and tumor necrosis factor alpha (TNF-α) production. Deficiency of Dectin-2 increased immune cell recruitment to the lungs but was dispensable for survival in a mouse model of pulmonary aspergillosis. Our results identify a novel interaction between galactomannan and Dectin-2 and demonstrate that Dectin-2 is a receptor for galactomannan, which leads to a proinflammatory immune response in the lung. IMPORTANCE Aspergillus fumigatus is a fungal pathogen that causes serious and often fatal disease in humans. The surface of Aspergillus is composed of complex sugar molecules. Recognition of these carbohydrates by immune cells by carbohydrate lectin receptors can lead to clearance of the infection or, in some cases, benefit the fungus by dampening the host response. Galactomannan is a carbohydrate that is part of the cell surface of Aspergillus but is also released during infection and is found in patient lungs as well as their bloodstreams. The significance of our research is that we have identified Dectin-2 as a mammalian immune cell receptor that recognizes, binds, and signals in response to galactomannan. These results enhance our understanding of how this carbohydrate interacts with the immune system at the site of infection and will lead to broader understanding of how release of galactomannan by Aspergillus effects the immune response in infected patients.

Deferoxamine prevents poststroke memory impairment in female diabetic rats: potential links to hemorrhagic transformation and ferroptosis.

Diabetes increases the risk of poststroke cognitive impairment (PSCI). Greater hemorrhagic transformation (HT) after stroke is associated with vasoregression and cognitive decline in male diabetic rats. Iron chelator deferoxamine (DFX) prevents vasoregression and improves outcomes. Although diabetic female rats develop greater HT, its impact on poststroke cerebrovascularization and cognitive outcomes remained unknown. We hypothesized that diabetes mediates pathological neovascularization, and DFX attenuates poststroke cerebrovascular remodeling and improves neurological outcomes in female diabetic rats. Female control and diabetic animals were treated with DFX or vehicle for 7 days after stroke. Vascular indices, microglial activation, and blood-brain barrier (BBB) integrity were evaluated on day 14. Results from diabetic female rats were partially compared with our previously published findings in male counterparts. Hemin-induced programmed cell death was studied in male and female brain microvascular endothelial cell lines (BMVEC). There was no vasoregression after stroke in either control or diabetic female animals. DFX prevented diabetes-mediated gliovascular remodeling and compromised BBB integrity while improving memory function in diabetes. Comparisons of female and male rats indicated sex differences in cognitive and vascular outcomes. Hemin mediated ferroptosis in both male and female BMVECs. DFX improved survival but had differential effects on ferroptosis signaling in female and male cells. These results suggest that stroke and associated HT do not affect cerebrovascularization in diabetic female rats, but iron chelation may provide a novel therapeutic strategy in the prevention of poststroke memory impairment in females with diabetes via the preservation of gliovascular integrity and improvement of endothelial cell survival.NEW & NOTEWORTHY The current study shows for the first time that diabetes does not promote aberrant cerebrovascularization in female rats. This contrasts with what we reported in male animals in various diabetes models. Deferoxamine preserved recognition memory function in diabetic female animals after stroke. The effect(s) of stroke and deferoxamine on cerebrovascular density and microglial activation also appear(s) to be different in female diabetic rats. Lastly, deferoxamine exerts detrimental effects on animals and BMVECs under control conditions.

Alcohol-related brain damage: A mixed-method evaluation of an online awareness-raising programme for frontline care and support practitioners.

INTRODUCTION: Alcohol-related brain damage (ARBD) is an umbrella term referring to the neurocognitive impairments caused by excessive and prolonged alcohol use and the associated nutritional deficiencies. This study evaluated the outcomes of an online research-informed training program for ARBD which aimed to improve client outcomes by promoting support staff's awareness and confidence in working with clients who may have (or who are at risk of developing) the condition. METHODS: Staff working within a large non-governmental non-profit housing organisation (n = 883) enrolled in the training program. Questionnaires were used pre- and post-training to collect self-reported awareness of ARBD and confidence in supporting individuals with the condition. Semi-structured interviews were conducted with 27 staff members approximately 10 weeks post-completion of the program. Interviews were audio-recorded, transcribed verbatim and analysed by employing qualitative content analysis. RESULTS: Findings from the questionnaires indicated a significant increase in all measures after completing the training program. Three main themes were developed based on the interview data: changes to awareness and understanding; professional practice; and training-specific characteristics. Participants reported changes in their ability to identify potential service users with ARBD and confidence in doing so. DISCUSSION AND CONCLUSION: Our findings demonstrate that online training programs can be effective in improving support staff's ability to identify ARBD, potentially leading an increase in signposting service users to relevant services. The research-informed nature of the training demonstrates that translating research findings directly to frontline workers can have a substantial impact and may improve outcomes for this client group.

Sonothrombolysis: State-of-the-Art and Potential Applications in Children.

In recent years, advances in ultrasound therapeutics have been implemented into treatment algorithms for the adult population; however, the use of therapeutic ultrasound in the pediatric population still needs to be further elucidated. In order to better characterize the utilization and practicality of sonothrombolysis in the juvenile population, the authors conducted a literature review of current pediatric research in therapeutic ultrasound. The PubMed database was used to search for all clinical and preclinical studies detailing the use and applications of sonothrombolysis, with a focus on the pediatric population. As illustrated by various review articles, case studies, and original research, sonothrombolysis demonstrates efficacy and safety in clot dissolution in vitro and in animal studies, particularly when combined with microbubbles, with potential applications in conditions such as deep venous thrombosis, peripheral vascular disease, ischemic stroke, myocardial infarction, and pulmonary embolism. Although there is limited literature on the use of therapeutic ultrasound in children, mainly due to the lower prevalence of thrombotic events, sonothrombolysis shows potential as a noninvasive thrombolytic treatment. However, more pediatric sonothrombolysis research needs to be conducted to quantify the safety and ethical considerations specific to this vulnerable population.

Cloud-controlled microscopy enables remote project-based biology education in underserved Latinx communities.

Project-based learning (PBL) has long been recognized as an effective way to teach complex biology concepts. However, not all institutions have the resources to facilitate effective project-based coursework for students. We have developed a framework for facilitating PBL using remote-controlled internet-connected microscopes. Through this approach, one lab facility can host an experiment for many students around the world simultaneously. Experiments on this platform can be run on long timescales and with materials that are typically unavailable to high school classrooms. This allows students to perform novel research projects rather than just repeating standard classroom experiments. To investigate the impact of this program, we designed and ran six user studies with students worldwide. All experiments were hosted in Santa Cruz and San Francisco, California, with observations and decisions made remotely by the students using their personal computers and cellphones. In surveys gathered after the experiments, students reported increased excitement for science and a greater desire to pursue a career in STEM. This framework represents a novel, scalable, and effective PBL approach that has the potential to democratize biology and STEM education around the world.