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Abstract Smartphone applications are one of the main delivery modalities in digital health. Many of these mHealth apps use gamification to engage users, improve user experience, and achieve better health outcomes. Yet, it remains unclear whether gamified approaches help to deliver effective, safe, and clinically beneficial products to users. This study examines the compliance of 69 gamified mHealth apps with the EU Medical Device Regulation and assesses the specific risks arising from the gamified nature of these apps. Of the identified apps, 32 (46.4%) were considered non-medical devices; seven (10.1%) were already cleared/approved by the regulatory authorities, and 31 (44.9%) apps were assessed as likely non-compliant or potentially non-compliant with regulatory requirements. These applications and one approved application were assessed as on the market without the required regulatory approvals. According to our analysis, a higher proportion of these apps would be classified as medical devices in the US. The level of risk posed by gamification remains ambiguous. While most apps showed only a weak link between the degree of gamification and potential risks, this link was stronger for those apps with a high degree of gamification or an immersive game experience.

Abstract AidData’s Global Chinese Development Finance Dataset (Version 3.0) provides detailed information about more than 20,000 development projects across 165 low- and middle-income countries financed by 791 official sector Chinese donors and lenders from 2000 to 2021. In this study, we introduce a methodology for identifying the geospatial features of these projects. Our application of the methodology has resulted in the Geospatial Global Chinese Development Finance Dataset (Version 3.0), which captures the geospatial features of 9,405 projects across 148 low- and middle-income countries supported by Chinese grant and loan commitments worth more than USD 830 billion. The dataset provides details for 6,266 projects containing spatial definitions of roads, railways, power plants, transmission lines, buildings, and other precisely geocoded features. It identifies approximate and administrative-level locations for 3,139 additional projects. The methodology, dataset, and the code used to construct the dataset have been made publicly available to facilitate replication and future applications.

Abstract: Eicosanoids are a class of molecules derived from C20 polyunsaturated fatty acids (PUFAs) that play a vital role in mammalian and insect biological systems, including development, reproduction, and immunity. Recent research has shown that insects have significant but lower levels of C20 PUFAs in circulation in comparison to C18 PUFAs. It has been previously hypothesized in insects that eicosanoids are synthesized from C18 precursors, such as linoleic acid (LA), to produce downstream eicosanoids. In this study, we show that introduction of arachidonic acid (AA) stimulates production of cyclooxygenase, lipoxygenase, and cytochrome P450–derived eicosanoids. Downstream immune readouts showed that LA stimulates phagocytosis by hemocytes, while both LA and AA stimulate increased antimicrobial peptide production when D. melanogaster is exposed to a heat-killed bacterial pathogen. In totality, this work identifies PUFAs that are involved in insect immunity and adds evidence to the notion that Drosophila utilizes immunostimulatory lipid signaling to mitigate bacterial infections. Our understanding of immune signaling in the fly and its analogies to mammalian systems will increase the power and value of Drosophila as a model organism in immune studies.

Abstract Background Advanced paternal age (APA) is associated with adverse outcomes to offspring health, including increased risk for neurodevelopmental disorders. The aim of this study was to investigate the methylome and transcriptome of the first two early embryonic tissue lineages, the inner cell mass (ICM) and the trophectoderm (TE), from human blastocysts in association with paternal age and disease risk. High quality human blastocysts were donated with patient consent from donor oocyte IVF cycles from either APA (≥ 50 years) or young fathers. Blastocysts were mechanically separated into ICM and TE lineage samples for both methylome and transcriptome analyses. Results Significant differential methylation and transcription was observed concurrently in ICM and TE lineages of APA-derived blastocysts compared to those from young fathers. The methylome revealed significant enrichment for neuronal signaling pathways, as well as an association with neurodevelopmental disorders and imprinted genes, largely overlapping within both the ICM and TE lineages. Significant enrichment of neurodevelopmental signaling pathways was also observed for differentially expressed genes, but only in the ICM. In stark contrast, no significant signaling pathways or gene ontology terms were identified in the trophectoderm. Despite normal semen parameters in aged fathers, these significant molecular alterations can adversely contribute to downstream impacts on offspring health, in particular neurodevelopmental disorders like autism spectrum disorder and schizophrenia. Conclusions An increased risk for neurodevelopmental disorders is well described in children conceived by aged fathers. Using blastocysts derived from donor oocyte IVF cycles to strategically control for maternal age, our data reveals evidence of methylation dysregulation in both tissue lineages, as well as transcription dysregulation in neurodevelopmental signaling pathways associated with APA fathers. This data also reveals that embryos derived from APA fathers do not appear to be compromised for initial implantation potential with no significant pathway signaling disruption in trophectoderm transcription. Collectively, our work provides insights into the complex molecular mechanisms that occur upon paternal aging during the first lineage differentiation in the preimplantation embryo. Early expression and epigenetic markers of APA-derived preimplantation embryos highlight the susceptibility of the future fetus to adverse health outcomes.

Abstract The work function is a critical parameter for device design and understanding of materials properties, but contemporary experimental literature on tailored work functions is rather scarce. This paper presents a promising new approach to work function design that uses pulsed laser deposition (PLD) growth with unit cell precision. It is shown that a monolayer buried within a material can influence the work function as a function of the layer depth. This method can preserve properties of the original material's surface, and furthermore, a sensitive material can be used as the monolayer, both of which are beneficial for device design. Proof of concept is demonstrated by inserting a nominal monolayer of barium oxide (BaO) into strontium titanate (SrTiO3) (001) at different depths, revealing a previously unknown work function trend. Density functional theory (DFT) calculations, surface characterization, and scanning transmission electron microscopy (STEM) studies verify the quality of the heterostructures and help to understand how charge transfer, slight barium diffusion, and termination effects account for the observed work function trends. This work function tunability is a promising approach for future devices that require a tailored work function, which can easily be extended to a wider variety of materials.

Abstract Epithelial plasticity has been suggested in lungs of mice following genetic depletion of stem cells but is of unknown physiological relevance. Viral infection and chronic lung disease share similar pathological features of stem cell loss in alveoli, basal cell (BC) hyperplasia in small airways, and innate immune activation, that contribute to epithelial remodeling and loss of lung function. We show that a subset of distal airway secretory cells, intralobar serous (IS) cells, are activated to assume BC fates following influenza virus infection. Injury-induced hyperplastic BC (hBC) differ from pre-existing BC by high expression of IL-22Ra1 and undergo IL-22-dependent expansion for colonization of injured alveoli. Resolution of virus-elicited inflammation results in BC to IS re-differentiation in repopulated alveoli, and increased local expression of protective antimicrobial factors, but fails to restore normal alveolar epithelium responsible for gas exchange.

Abstract Objective This study delineates the clinical and molecular spectrum of ANKLE2‐related microcephaly (MIC), as well as highlights shared pathological mechanisms between ANKLE2 and the Zika virus. Methods We identified 12 individuals with MIC and variants in ANKLE2 with a broad range of features. Probands underwent thorough phenotypic evaluations, developmental assessments, and anthropometric measurements. Brain imaging studies were systematically reviewed for developmental abnormalities. We functionally interrogated a subset of identified ANKLE2 variants in Drosophila melanogaster. Results All individuals had MIC (z‐score ≤ −3), including nine with congenital MIC. We identified a broad range of brain abnormalities including simplified cortical gyral pattern, full or partial callosal agenesis, increased extra‐axial spaces, hypomyelination, cerebellar vermis hypoplasia, and enlarged cisterna magna. All probands had developmental delays in at least one domain, with speech and language delays being the most common. Six probands had skin findings characteristic of ANKLE2 including hyper‐ and hypopigmented macules. Only one individual had scalp rugae. Functional characterization in Drosophila recapitulated the human MIC phenotype. Of the four variants tested, p.Val229Gly, p.Arg236*, and p.Arg536Cys acted as partial‐loss‐of‐function variants, whereas the c.1421‐1G>C splicing variant demonstrated a strong loss‐of‐function effect. Interpretation Deleterious variants in the ANKLE2 gene cause a unique MIC syndrome characterized by congenital or postnatal MIC, a broad range of structural brain abnormalities, and skin pigmentary changes. Thorough functional characterization has identified shared pathogenic mechanisms between ANKLE2‐related MIC and congenital Zika virus infection. This study further highlights the importance of a thorough diagnostic evaluation including molecular diagnostic testing in individuals with MIC.

Aging is a critical risk factor in idiopathic pulmonary fibrosis (IPF). Dysfunction and loss of type 2 alveolar epithelial cells (AEC2s) with failed regeneration is a seminal causal event in the pathogenesis of IPF, although the precise mechanisms for their regenerative failure and demise remain unclear. To systematically examine the genomic program changes of AEC2s in aging and after lung injury, we performed unbiased single-cell RNA-seq analyses of lung epithelial cells from uninjured or bleomycin-injured young and old mice, as well as from lungs of IPF patients and healthy donors. We identified three AEC2 subsets based on their gene signatures. Subset AEC2-1 mainly exist in uninjured lungs, while subsets AEC2-2 and AEC2-3 emerged in injured lungs and increased with aging. Functionally, AEC2 subsets are correlated with progenitor cell renewal. Aging enhanced the expression of the genes related to inflammation, stress responses, senescence, and apoptosis. Interestingly, lung injury increased aging-related gene expression in AEC2s even in young mice. The synergistic effects of aging and injury contributed to impaired AEC2 recovery in aged mouse lungs after injury. In addition, we also identified three subsets of AEC2s from human lungs that formed three similar subsets to mouse AEC2s. IPF AEC2s showed a similar genomic signature to AEC2 subsets from bleomycin-injured old mouse lungs. Taken together, we identified synergistic effects of aging and AEC2 injury in transcriptomic and functional analyses that promoted fibrosis. This study provides new insights into the interactions between aging and lung injury with interesting overlap with diseased IPF AEC2 cells.

Abstract Recent advances in single-cell RNA sequencing (scRNA-seq) and epithelium lineage labeling have yielded identification of multiple abnormal epithelial progenitor populations during alveolar type 2 (ATII) cell differentiation into alveolar type 1 (ATI) cells during regenerative lung post-fibrotic injury. These abnormal cells include basaloid/basal-like cells, ATII transition cells, and persistent epithelial progenitors (PEPs). These cells occurred and accumulated during the regeneration of distal airway and alveoli in response to both chronic and acute pulmonary injury. Among the alveolar epithelial progenitors, PEPs express a distinct Krt8 + phenotype that is rarely found in intact alveoli. However, post-injury, the Krt8 + phenotype is seen in dysplastic epithelial cells. Fully understanding the characteristics and functions of these newly found, injury-induced abnormal behavioral epithelial progenitors and the signaling pathways regulating their phenotype could potentially point the way to unique therapeutic targets for fibrosing lung diseases. This review summarizes recent advances in understanding these epithelial progenitors as they relate to uncovering regenerative mechanisms.

During chronic cystic fibrosis (CF) infections, evolved Pseudomonas aeruginosa antibiotic resistance is linked to increased pulmonary exacerbations, decreased lung function, and hospitalizations. However, the virulence mechanisms underlying worse outcomes caused by antibiotic resistant infections are poorly understood. Here, we investigated evolved aztreonam resistant P. aeruginosa virulence mechanisms. Using a macrophage infection model combined with genomic and transcriptomic analyses, we show that a compensatory mutation in the rne gene, encoding RNase E, increased pyoverdine and pyochelin siderophore gene expression, causing macrophage ferroptosis and lysis. We show that iron-bound pyochelin was sufficient to cause macrophage ferroptosis and lysis, however, apo-pyochelin, iron-bound pyoverdine, or apo-pyoverdine were insufficient to kill macrophages. Macrophage killing could be eliminated by treatment with the iron mimetic gallium. RNase E variants were abundant in clinical isolates, and CF sputum gene expression data show that clinical isolates phenocopied RNase E variant functions during macrophage infection. Together these data show how P. aeruginosa RNase E variants can cause host damage via increased siderophore production and host cell ferroptosis but may also be targets for gallium precision therapy.

A key aspect of parasitic nematode infection is the nematodes’ ability to evade and/or suppress host immunity. This immunomodulatory ability is likely driven by the release of hundreds of excretory/secretory proteins (ESPs) during infection. While ESPs have been shown to display immunosuppressive effects on various hosts, our understanding of the molecular interactions between individual proteins released and host immunity requires further study. We have recently identified a secreted phospholipase A2 (sPLA2) released from the entomopathogenic nematode (EPN) Steinernema carpocapsae we have named Sc-sPLA2. We report that Sc-sPLA2 increased mortality of Drosophila melanogaster infected with Streptococcus pneumoniae and promoted increased bacterial growth. Furthermore, our data showed that Sc-sPLA2 was able to downregulate both Toll and Imd pathway-associated antimicrobial peptides (AMPs) including drosomycin and defensin, in addition to suppressing phagocytosis in the hemolymph. Sc-sPLA2 was also found to be toxic to D. melanogaster with the severity being both dose- and time-dependent. Collectively, our data highlighted that Sc-sPLA2 possessed both toxic and immunosuppressive capabilities.

Type 2 alveolar epithelial cells (AEC2s) function as progenitor cells in the lung. We have shown previously that failure of AEC2 regeneration results in progressive lung fibrosis in mice and is a cardinal feature of idiopathic pulmonary fibrosis (IPF). In this study, we identified deficiency of a specific zinc transporter, SLC39A8 (ZIP8), in AEC2s from both IPF lungs and lungs of old mice. Loss of ZIP8 expression was associated with impaired renewal capacity of AEC2s and enhanced lung fibrosis. ZIP8 regulation of AEC2 progenitor function was dependent on SIRT1. Replenishment with exogenous zinc and SIRT1 activation promoted self-renewal and differentiation of AEC2s from lung tissues of IPF patients and old mice. Deletion of Zip8 in AEC2s in mice resulted in impaired AEC2 renewal, increased susceptibility to bleomycin injury, and development of spontaneous lung fibrosis. Therapeutic strategies to restore zinc metabolism and appropriate SIRT1 signaling could improve AEC2 progenitor function and mitigate ongoing fibrogenesis.

Social distancing, home confinement, economic challenges, and COVID-19-related illness and deaths during the COVID-19 pandemic can significantly affect mental health in youth. One promising approach to reduce anxiety and depression in adolescents is the neuroscience-based mindfulness intervention Training for Awareness, Resilience, and Action (TARA). The objective of this individually randomized waitlist-controlled trial (RCT) was (1) to test the feasibility of TARA, delivered partially over Zoom, and (2) to assess changes in the emotional wellbeing in healthy adolescents between the ages of 14–18 years old during the COVID-19 pandemic. Methods: Twenty-one healthy adolescents were randomized to the TARA intervention or to the waitlist control group in February 2020, just before the start of the pandemic. The TARA group intervention was delivered in person for the first five sessions and remotely over Zoom for the remaining seven sessions due to the pandemic. The participants’ acceptability of TARA was assessed weekly using the Child Session Rating Scale (CSRS). The primary outcome was the emotional wellbeing measured using emotional symptoms subscale of the Strengths and Difficulties Questionnaire (SDQ) pre/post-TARA. We also explored weekly changes in TARA participants’ wellbeing using the Child Outcome Rating Scale (CORS). Results: The overall session rating in TARA participants improved after the switch to Zoom (Cohen’s d = 1.2, p = 0.008). The results of the two-way ANOVA showed no statistically significant difference in the change of the SDQ emotional symptoms during the 12 weeks between the TARA group and waitlist-control group (timepoint × group interaction: F = 0.77, p = 0.38). The exploratory analysis using the CORS in the TARA participants showed a significant improvement in their functioning over the weeks of training. Conclusion: Our results support the feasibility of TARA delivered over Zoom. While our primary outcome did not provide support for the improvement of the emotional wellbeing with TARA compared to a passive control group, our exploratory analysis in the intervention group indicated an improved functioning over the weeks of TARA training. The important general positive impact of this study lies in the possibility of offering a neuroscience-based mindfulness intervention remotely to youth living in remote areas and for all youth during pandemic times.

Fatty acid–and retinol-binding proteins (FARs) belong to a unique family of excreted/secreted proteins (ESPs) found exclusively in nematodes. Much of our understanding of these proteins, however, is limited to their in vitro binding characteristics toward various fatty acids and retinol and has provided little insight into their in vivo functions or mechanisms. Recent research, however, has shown that FARs elicit an immunomodulatory role in plant and animal model systems, likely by sequestering lipids involved in immune signaling. This alludes to the intricate relationship between parasitic nematode effectors and their hosts.

Adolescence is a period of substantial neural and social development, and prosocial decisions are beneficial to personal well-being, the well-being of others, and the functioning of society. Advances in network neuroscience call for a systematic synthesis and reappraisal of prosocial neural correlates during adolescent development. In this systematic review, we aim to outline the progress made in this field, identify the similarities between study results, and propose a model for prosocial cognition in adolescents to young adults. A total of 25 articles were included in this review. After reviewing and synthesizing the literature, we propose a DOmain-General Developmental “Do-GooD” network model of prosocial cognition that aligns with the reviewed literature, accounts for development, and combines elements of the value-based decision-making model with distinct value contributions from the default mode network, salience network, and control network. We offer predictions to test the “Do-GooD” model and propose new future directions for studying prosocial behavior and its development during adolescence, which in turn may lead to improving education and the development of better health interventions for adolescents.

Digital mental health interventions (DMHI) are scalable and cost-effective strategies for increasing access to mental health care; however, dropout rates associated with digital interventions are high, particularly for open-access digital interventions. While some studies have focused on predictors of dropout from digital mental health programs, few studies have focused on engagement features that might improve engagement. In this perspective article, we discuss whether monetary incentives (MI) are one avenue to increasing user engagement in DMHI. We begin by reviewing the literature on the effects of MI for behavior change in health domains (e.g., dietary behaviors, substance use, and medication adherence). Then, drawing on a pilot study we conducted to test the effects of different levels of MI on usage and improvement in subjective well-being among users of a DMHI (Happify), we discuss the potential applications of MI for DMHI, the potential drawbacks of financial incentives in this context, and open questions for future research.

BackgroundThe American Heart Association has identified poor mental health as a key barrier to healthy behavior change for those with cardiovascular disease (CVD) risk factors such as high blood pressure, high cholesterol, and diabetes. Digital mental health interventions, like those delivered via the internet to computers or smartphones, may provide a scalable solution to improving the mental and physical health of this population. Happify is one such intervention and has demonstrated evidence of efficacy for improving aspects of mental health in both the general population and in users with chronic conditions. ObjectiveThe objectives of this analysis of real-world data from Happify users with self-reported CVD risk factors, including high blood pressure and cholesterol, diabetes, and heart disease, were to examine whether these users would report improvements in subjective well-being and anxiety over time (H1) and use of Happify as recommended would be associated with significantly greater improvement in subjective well-being and anxiety over time compared to less-than-recommended usage (H2). MethodsData were obtained from existing Happify users who reported the aforementioned CVD risk factors. The sample included 1803 users receiving at least 6 weeks’ exposure to Happify (ranging from 42 days to 182 days) who completed at least one activity and two assessments within the app during that time. Subjective well-being was assessed with the Happify Scale, a 9-item measure of positive emotionality and life satisfaction, and anxiety was assessed with the Generalized Anxiety Disorder 2 (GAD-2). To evaluate H1, changes over time in both outcomes were assessed using mixed effects linear regression models, controlling for demographics and usage. For H2, an interaction term was added to the models to assess whether usage as recommended was associated with greater improvement over time. ResultsBoth hypotheses were supported. For both the Happify scale and GAD-2, the initial multivariable model without an interaction demonstrated an effect for time from baseline, and the addition of the interaction term between time and recommended use was significant as well. ConclusionsThis analysis of real-world data provides preliminary evidence that Happify users with self-reported CVD risk factors including high blood pressure or cholesterol, diabetes, and heart disease experienced improved well-being and anxiety over time and that those who used Happify as recommended experienced greater improvements in these aspects of mental health than those who completed fewer activities. These findings extend previous research, which demonstrated that engagement with Happify as recommended was associated with improved well-being among physically healthy users and in those with chronic conditions, to a new population for whom mental health is especially critical: those at risk of developing CVD.

Parasitic nematodes cause significant morbidity and mortality globally. Excretory/secretory products (ESPs) such as fatty acid- and retinol- binding proteins (FARs) are hypothesized to suppress host immunity during nematode infection, yet little is known about their interactions with host tissues. Leveraging the insect parasitic nematode, Steinernema carpocapsae, we describe here the first in vivo study demonstrating that FARs modulate animal immunity, causing an increase in susceptibility to bacterial co-infection. Moreover, we show that FARs dampen key components of the fly immune response including the phenoloxidase cascade and antimicrobial peptide (AMP) production. Our data also reveal that FARs deplete lipid signaling precursors in vivo as well as bind to these fatty acids in vitro, suggesting that FARs elicit their immunomodulatory effects by altering the availability of lipid signaling molecules necessary for an efficient immune response. Collectively, these data support a complex role for FARs in immunosuppression in animals and provide detailed mechanistic insight into parasitism in phylum Nematoda.

Summary: Pulmonary mesenchymal cells are critical players in both the mouse and human during lung development and disease states. They are increasingly recognized as highly heterogeneous, but there is no consensus on subpopulations or discriminative markers for each subtype. We completed scRNA-seq analysis of mesenchymal cells from the embryonic, postnatal, adult and aged fibrotic lungs of mice and humans. We consistently identified and delineated the transcriptome of lipofibroblasts, myofibroblasts, smooth muscle cells, pericytes, mesothelial cells, and a novel population characterized by Ebf1 expression. Subtype selective transcription factors and putative divergence of the clusters during development were described. Comparative analysis revealed orthologous subpopulations with conserved transcriptomic signatures in murine and human lung mesenchymal cells. All mesenchymal subpopulations contributed to matrix gene expression in fibrosis. This analysis would enhance our understanding of mesenchymal cell heterogeneity in lung development, homeostasis and fibrotic disease conditions.

Mindfulness-based approaches show promise to improve emotional health in youth and may help treat and prevent adolescent depression and anxiety. However, there is a fundamental gap in understanding the neural reorganization that takes place as a result of such interventions. The Training for Awareness, Resilience, and Action (TARA) program, initially developed for depressed adolescents, uses a framework drawn from neuroscience, mindfulness, yoga, and modern psychotherapeutic techniques to promote emotional health. The goal of this study was to assess the effects of the TARA training on emotional health and structural white matter brain networks in healthy youth. We analyzed data from 23 adolescents who underwent the 12-week TARA training in a controlled within-subject study design and whose brain networks were assessed using diffusion MRI connectomics. Compared to the control time period, adolescents showed a significant decrease in anxiety symptoms with TARA (Cohen’s d = -0.961, p = 0.006); moreover, the node strength of the Right Amygdala decreased significantly after TARA (Cohen’s d = -1.026, p = 0.004). Post-hoc analyses indicated that anxiety at baseline before TARA was positively correlated with Right Amygdala node strength (r = 0.672, p = 0.001). While change in Right Amygdala node strength with TARA was not correlated with change in anxiety (r = 0.146, p = 0.51), it was associated with change in depression subscale of Anhedonia / Negative Affect (r = 0.575, p = 0.004, exploratory analysis), possibly due to overlapping constructs captured in our anxiety and depression scales. Our results suggest that increased structural connectivity of Right Amygdala may underlie increased anxiety in adolescents and be lowered through anxiety-reducing training such as TARA. The results of this study contribute to our understanding of the neural mechanisms of TARA and may facilitate neuroscience-based prevention and treatment of adolescent anxiety and depression.

The red-shouldered soapberry bug, Jadera haematoloma, is a potential model system for developmental plasticity. Here, the authors show that the reaction norm for wing polyphenism has evolved in a recently derived ecotype and identify insulin signaling as a candidate pathway underlying this adaptive change.

The placental epigenome plays a critical role in regulating mammalian growth and development. Alterations to placental methylation, often observed at imprinted genes, can lead to adverse pregnancy complications such as intrauterine growth restriction and preterm birth. Similar associations have been observed in offspring derived from advanced paternal age fathers. As parental age at time of conception continues to rise, the impact of advanced paternal age on these reproductive outcomes is a growing concern, but limited information is available on the molecular mechanisms affected in utero. This longitudinal murine research study thus investigated the impact of paternal aging on genomic imprinting in viable F1 embryonic portions of the placentas derived from the same paternal males when they were young (4-6 months) and when they aged (11-15 months). The use of a controlled outbred mouse model enabled analysis of offspring throughout the natural lifetime of the same paternal males and excluded confounding factors like female age or infertility. Firstly, paternal age significantly impacted embryonic placental weight, fetal weight and length. Targeted bisulfite sequencing was utilized to examine imprinted methylation at the Kcnq1ot1 imprinting control region, with significant hypermethylation observed upon natural paternal aging. Quantitative real-time PCR assessed imprinted gene expression levels at various imprinting clusters, resulting in transcript level alterations attributable to advanced paternal age. In summary, our results demonstrate a paternal age effect with dysregulation at numerous imprinted loci, providing a mechanism for future adverse placental and offspring health conditions.

Advanced maternal age (AMA) is associated with reduced fertility due in part to diminished ovarian follicle quantity, inferior oocyte quality, chromosome aneuploidy, and lower implantation rates. Ovarian aging is accompanied by increased oxidative stress and blunted antioxidant signaling, such that antioxidant intervention could improve reproductive potential. The first aim of this study was to determine the molecular effects of antioxidant intervention in the ovaries and oocytes of aged mice, utilizing a supplement containing only naturally occurring açaí (Euterpe oleracea) with an oxygen radical absorbance capacity of 208,628 μmol Trolox equivalent (TE)/100 g indicating high antioxidant activity. Nine month old female CF-1 mice were administered 80 mg/day antioxidants (n = 12) or standard diet (n = 12) for 12 weeks. In the ovary, antioxidant treatment upregulated β-adrenergic signaling, downregulated apoptosis and proinflammatory signaling, and variably affected cell growth and antioxidant pathways (p < 0.05). Exogenous antioxidants also increased the oocyte expression of antioxidant genes GPX1, SOD2, and GSR (p < 0.05). A feasibility analysis was then conducted on female AMA infertility patients as a proof-of-principle investigation. Patients (n = 121;

Using an in vivo model of tolerance to TLR7-induced skin inflammation, we found a critical role for macrophage-derived MMP10 in mediating immune hypo-responsiveness. Cutaneous exposure to Imiquimod (IMQ), a TLR7 agonist, induced acute expression of pro-inflammatory factors (IL1β, IL6, CXCL1) and neutrophil influx equally in both wildtype and Mmp10−/− mice. However, whereas subsequent exposure (11 and 12 days later) to IMQ led to marked abrogation of pro-inflammatory factor expression in wildtype mice, Mmp10−/− mice responded similarly as they did to the first application. In addition, the second exposure led to increased expression of negative regulators of TLR signaling (TNFAIP3, IRAK3) and immunosuppressive cytokines (IL10, TGFβ1) in wildtype mice but not in Mmp10−/− mice. In vitro studies demonstrated that prior exposure of IMQ to bone marrow-derived macrophages (BMDM) made wildtype cells refractory to subsequent stimulation but did not for Mmp10−/− macrophages. These findings expand the critical roles MMP10 plays in controlling macrophage activation to indicate that the development of immune tolerance to TLR7 ligand is dependent on this macrophage-derived proteinase.