Enhancing immune cell functions in tumors remains a major challenge in cancer immunotherapy. Hypoxia is a common feature of solid tumors, and cells adapt by upregulating the transcription factor ...HIF-1α. Here, we defined the transcriptional landscape of mouse tumor-infiltrating natural killer (NK) cells by using single-cell RNA sequencing. Conditional deletion of Hif1a in NK cells resulted in reduced tumor growth, elevated expression of activation markers, effector molecules, and an enriched NF-κB pathway in tumor-infiltrating NK cells. Interleukin-18 (IL-18) from myeloid cells was required for NF-κB activation and the enhanced anti-tumor activity of Hif1a−/− NK cells. Extended culture with an HIF-1α inhibitor increased human NK cell responses. Low HIF1A expression was associated with high expression of IFNG in human tumor-infiltrating NK cells, and an enriched NK-IL18-IFNG signature in solid tumors correlated with increased overall patient survival. Thus, inhibition of HIF-1α unleashes NK cell anti-tumor activity and could be exploited for cancer therapy.
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•Hif1a deficiency in NK cells reduces tumor growth•Single-cell RNA sequencing reveals activated Hif1a−/− NK cells in tumor•IL-18 drives high NF-κB, Iκbζ, and Ifng expression in tumor HIF1a−/− NK cells•An NK-IL18-IFNGhi signature correlates with increased survival in cancer patients
Ni et al. define the transcriptional landscape of tumor-infiltrating NK cells using single-cell RNA sequencing. They find that the transcription factor HIF-1α suppresses IL-18-driven NF-κB signaling and anti-tumor activity of tumor-infiltrating NK cells. Extended inhibition of HIF-1α in mouse or human NK cells unleashes potent NK cell effector function.
‘Angiodiversity’ refers to the structural and functional heterogeneity of endothelial cells (EC) along the segments of the vascular tree and especially within the microvascular beds of different ...organs. Organotypically differentiated EC ranging from continuous, barrier-forming endothelium to discontinuous, fenestrated endothelium perform organ-specific functions such as the maintenance of the tightly sealed blood–brain barrier or the clearance of macromolecular waste products from the peripheral blood by liver EC-expressed scavenger receptors. The microvascular bed of the liver, composed of discontinuous, fenestrated liver sinusoidal endothelial cells (LSEC), is a prime example of organ-specific angiodiversity. Anatomy and development of LSEC have been extensively studied by electron microscopy as well as linage-tracing experiments. Recent advances in cell isolation and bulk transcriptomics or single-cell RNA sequencing techniques allowed the identification of distinct LSEC molecular programs and have led to the identification of LSEC subpopulations. LSEC execute homeostatic functions such as fine tuning the vascular tone, clearing noxious substances from the circulation, and modulating immunoregulatory mechanisms. In recent years, the identification and functional analysis of LSEC-derived angiocrine signals, which control liver homeostasis and disease pathogenesis in an instructive manner, marks a major change of paradigm in the understanding of liver function in health and disease. This review summarizes recent advances in the understanding of liver vascular angiodiversity and the functional consequences resulting thereof.
Postnatal liver development is characterized by hepatocyte growth, proliferation, and functional maturation. Notably, canonical Wnt signaling in hepatocytes has been identified as an important ...regulator of final adult liver size and metabolic liver zonation. The cellular origin of Wnt ligands responsible for homeostatic liver/body weight ratio (LW/BW) remained unclear, which was also attributable to a lack of suitable endothelial Cre driver mice. To comprehensively analyze the effects of hepatic angiocrine Wnt signaling on liver development and metabolic functions, we used endothelial subtype‐specific Stab2‐Cre driver mice to delete Wls from hepatic endothelial cells (HECs). The resultant Stab2‐Cretg/wt;Wlsfl/fl (Wls‐HECKO) mice were viable, but showed a significantly reduced LW/BW. Specifically, ablation of angiocrine Wnt signaling impaired metabolic zonation in the liver, as shown by loss of pericentral, β‐catenin‐dependent target genes such as glutamine synthase (Glul), RhBg, Axin2, and cytochrome P450 2E1, as well as by extended expression of periportal genes such as arginase 1. Furthermore, endothelial subtype‐specific expression of a c‐terminally YFP‐tagged Wls fusion protein in Wls‐HECKO mice (Stab2‐Cretg/wt;Wlsfl/fl;Rosa26:Wls‐YFPfl/wt Wls‐rescue) restored metabolic liver zonation. Interestingly, lipid metabolism was altered in Wls‐HECKO mice exhibiting significantly reduced plasma cholesterol levels, while maintaining normal plasma triglyceride and blood glucose concentrations. On the contrary, zonal expression of Endomucin, LYVE1, and other markers of HEC heterogeneity were not altered in Wls‐HECKO livers. Conclusion: Angiocrine Wnt signaling controls liver growth as well as development of metabolic liver zonation in mice, whereas intrahepatic HEC zonation is not affected. (Hepatology 2017).
Aim
This study addresses the scarcity of longitudinal research on the influence of screen media on children. It aims to explore the longitudinal relationship between children's vocabulary development ...and their exposure to screen media.
Methods
The study, initiated in 2017, included 72 children (37 boys) in Östergötland, Sweden, at three key developmental stages: preverbal (9.7 months), early verbal (25.5 months) and preliterate (5.4 years). Parents completed online surveys at each time point, reporting their child's screen time. At 10 months and 2 years, age‐appropriate vocabulary assessments were conducted online. At age 5, children's vocabulary was laboratory assessed.
Results
Correlational analysis revealed a negative relationship between language scores and screen media use across all time points. Furthermore, a cross‐lagged panel model demonstrated that screen media use showed significant continuity over time, with screen use at age 2 predicting language development at ages 2 and 5.
Conclusion
This longitudinal study, spanned from 9 months to 5 years of age, established a predictive negative association between children's exposure to screen media and their vocabulary development. These findings underscore the need to consider the impact of screen media on early childhood development and may inform guidelines for screen media use in young children.
Angiocrine signaling by liver sinusoidal endothelial cells (LSECs) regulates hepatic functions such as growth, metabolic maturation, and regeneration. Recently, we identified GATA4 as the master ...regulator of LSEC specification during development. Herein, we studied the role of endothelial GATA4 in the adult liver and in hepatic pathogenesis.
We generated adult Clec4g-icretg/0xGata4fl/fl (Gata4LSEC-KO) mice with LSEC-specific depletion of Gata4. Livers were analyzed by histology, electron microscopy, immunohistochemistry/immunofluorescence, in situ hybridization, and LSECs were isolated for gene expression profiling, ChIP- and ATAC-sequencing. Partial hepatectomy was performed to assess regeneration. We used choline-deficient, l-amino acid-defined (CDAA) diet and chronic carbon tetrachloride exposure to model liver fibrosis. Human single cell RNA-seq data sets were analyzed for endothelial alterations in healthy and cirrhotic livers.
Genetic Gata4 deficiency in LSECs of adult mice caused perisinusoidal liver fibrosis, hepatopathy and impaired liver regeneration. Sinusoidal capillarization and LSEC-to-continuous endothelial transdifferentiation were accompanied by a profibrotic angiocrine switch involving de novo endothelial expression of hepatic stellate cell-activating cytokine PDGFB. Increased chromatin accessibility and amplification by activated MYC mediated angiocrine Pdgfb expression. As observed in Gata4LSEC-KO livers, CDAA diet-induced perisinusoidal liver fibrosis was associated with GATA4 repression, MYC activation and a profibrotic angiocrine switch in LSECs. Comparison of CDAA-fed Gata4LSEC-KO and control mice demonstrated that endothelial GATA4 indeed protects against dietary-induced perisinusoidal liver fibrosis. In human cirrhotic livers, GATA4-positive LSECs and endothelial GATA4 target genes were reduced, while non-LSEC endothelial cells and MYC target genes including PDGFB were enriched.
Endothelial GATA4 protects against perisinusoidal liver fibrosis by repressing MYC activation and profibrotic angiocrine signaling at the chromatin level. Therapies targeting the GATA4/MYC/PDGFB/PDGFRβ axis offer a promising strategy for prevention and treatment of liver fibrosis.
The liver vasculature is supposed to play a major role in the development of liver fibrosis and cirrhosis, which can lead to liver failure and liver cancer. Herein, we discovered that structural and transcriptional changes induced by genetic deletion of the transcription factor GATA4 in the hepatic endothelium were sufficient to cause liver fibrosis. Activation of the transcription factor MYC and de novo expression of the “angiocrine” growth factor PDGFB were identified as downstream drivers of fibrosis and as potential therapeutic targets for this potentially fatal disease.
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•Genetic endothelial Gata4 deletion leads to liver fibrosis and hepatopathy.•Gata4 deficiency causes profibrotic angiocrine signaling via endothelial PDGFB.•Increased chromatin accessibility and activated MYC mediate Pdgfb expression in LSECs.•Dietary liver fibrosis causes dysregulation of the endothelial GATA4/MYC/PDGFB axis.•In human cirrhosis, single-cell data implicate the GATA4/PDGFB axis.
Although prior research has independently linked vocabulary development with toddlers' media usage, parental mental state talk (MST), and parent–child conversational turn‐taking (CTT), these ...variables have not been investigated within the same study. In this study, we focus on associations between these variables and 2‐year‐old's (N = 87) vocabulary. Child vocabulary and digital media use were measured through online questionnaires. We took a multimethod approach to measure parents' child‐directed talk. First, we used a home sound environment recording (Language ENvironment Analysis technology) to estimate parents' talk (CTT). Second, parents narrated a picture book, the Frog story, to assess the parent's MST. There was a negative association between how much children watched video content and their vocabulary. However, parents reported that they frequently co‐viewed and engaged with the child and media. The negative association first displayed between the amount of video content viewed and the child's developing vocabulary was fully mediated by the parents' qualitative and quantitative talk as measured by MST and CCT, respectively. We propose that the parent relative level of MST and CTT also occurs when parents engage with the child during media use.
Digital media availability has surged over the past decade. Because of a lack of comprehensive measurement tools, this rapid growth in access to digital media is accompanied by a scarcity of research ...examining the family media context and sociocognitive outcomes. There is also little cross-cultural research in families with young children. Modern media are mobile, interactive, and often short in duration, making them difficult to remember when caregivers respond to surveys about media use. The Comprehensive Assessment of Family Media Exposure (CAFE) Consortium has developed a novel tool to measure household media use through a web-based questionnaire, time-use diary, and passive-sensing app installed on family mobile devices. The goal of developing a comprehensive assessment of family media exposure was to take into account the contextual factors of media use and improve upon the limitations of existing self-report measures, while creating a consistent, scalable, and cost-effective tool. The CAFE tool captures the content and context of early media exposure and addresses the limitations of prior media measurement approaches. Preliminary data collected using this measure have been integrated into a shared visualization platform. In this perspective article, we take a tools-of-the-trade approach (
Oakes, 2010
) to describe four challenges associated with measuring household media exposure in families with young children: measuring attitudes and practices; capturing content and context; measuring short bursts of mobile device usage; and integrating data to capture the complexity of household media usage. We illustrate how each of these challenges can be addressed with preliminary data collected with the CAFE tool and visualized on our dashboard. We conclude with future directions including plans to test reliability, validity, and generalizability of these measures.
In this paper, the damping effect of granular materials is explored to reduce the vibration and noise of mechanical structures. To this end, a honeycomb structure with high stiffness is used to ...contain a granular filling which presents the possiblity for the distribution of the granular material to be designed. As a particular application example, the oil pan bottom of a combustion engine is used to investigate the influence on the vibration behavior and the sound emission. The effect of the honeycomb structure along with the granular mass, distribution, and type on the vibration behaviour of the structure is investigated via laser scanning vibrometry. From this, an optimized filling is determined and then its noise suppression level validated on an engine test bench through measurements with an acoustic array.
Digital media (DM), such as cellphones and tablets, are a common part of our daily lives and their usage has changed the communication structure within families. Thus, there is a risk that the use of ...DM might result in fewer opportunities for interactions between children and their parents leading to fewer language learning moments for young children. The current study examined the associations between children's language development and early DM exposure.
Ninety-two parents of 25months olds (50 boys/42 girls) recorded their home sound environment during a typical day Language ENvironment Analysis (LENA) and participated in an online questionnaire consisting of questions pertaining to daily DM use and media mediation strategies, as well as a Swedish online version of the MacArthur Communicative Development Inventory, which includes a vocabulary scale as well as a grammar and pragmatics scale.
Through correlations and stepwise regressions three aspects of language were analyzed. The child's vocabulary was positively associated with interactional turn-taking. The child's vocabulary and grammar were negatively associated with the likelihood of parent's device use during everyday child routines and the amount of TV watched by the child. The child's pragmatic development was also positively associated with the parent's device use in child routines but also with the parent's joint media engagement (JME), as well as the child's gender (where girls perform better).
Our study confirms that specific aspects of the 2-year old's DM environment are associated with the child's language development. More TV content, whether it is viewed on a big screen or tablet, is negatively associated with language development. The likelihood of parents' use of DM during everyday child routines is also negatively associated with the child's language development. Positive linguistic parental strategies such as interactional turn-taking with the child, JME, and book reading, on the other hand, are positively associated with the child's language development.
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