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Introduction Lymphedema is a common disease worldwide, with no cure and variable response to interventions. It may occur as the result of mutations in genes involved in lymphatic development or [...], Lymphedema is a debilitating disease with no effective cure and affects an estimated 250 million individuals worldwide. Prior studies have identified mutations in piezo-type mechanosensitive ion channel component 1 (PIEZO1), angiopoietin 2 (ANGPT2), and tyrosine kinase with Ig-like and EGF-like domains 1 (TIE1) in patients with primary lymphedema. Here, we identified crosstalk between these molecules and showed that activation of the mechanosensory channel PIEZO1 in lymphatic endothelial cells (LECs) caused rapid exocytosis of the TIE ligand ANGPT2, ectodomain shedding of TIE1 by disintegrin and metalloproteinase domain-containing protein 17 (ADAM17), and increased TIE/PI3K/AKT signaling, followed by nuclear export of the transcription factor FOXO1. These data establish a functional network between lymphedema-associated genes and provide what we believe to be the first molecular mechanism bridging channel function with vascular signaling and intracellular events culminating in transcriptional regulation of genes expressed in LECs. Our study provides insights into the regulation of lymphatic function and molecular pathways involved in human disease.

Introduction Vascular malformations are caused by genetic defects in endothelial cells (ECs) that line the interior of blood and lymphatic vessels. Most vascular anomalies arise during early vascular development and [...], Molecular characterization of vascular anomalies has revealed that affected endothelial cells (ECs) harbor gain-of-function (GOF) mutations in the gene encoding the catalytic a subunit of PI3K[alpha] (PIK3CA). These PIK3CA mutations are known to cause solid cancers when occurring in other tissues. PIK3CA-related vascular anomalies, or "PIKopathies," range from simple, i.e., restricted to a particular form of malformation, to complex, i.e., presenting with a range of hyperplasia phenotypes, including the PIK3CA-related overgrowth spectrum. Interestingly, development of PIKopathies is affected by fluid shear stress (FSS), a physiological stimulus caused by blood or lymph flow. These findings implicate PI3K in mediating physiological EC responses to FSS conditions characteristic of lymphatic and capillary vessel beds. Consistent with this hypothesis, increased PI3K signaling also contributes to cerebral cavernous malformations, a vascular disorder that affects low- perfused brain venous capillaries. Because the GOF activity of PI3K and its signaling partners are excellent drug targets, understanding PIK3CA's role in the development of vascular anomalies may inform therapeutic strategies to normalize EC responses in the diseased state. This Review focuses on PIK3CA's role in mediating EC responses to FSS and discusses current understanding of PIK3CA dysregulation in a range of vascular anomalies that particularly affect low-perfused regions of the vasculature. We also discuss recent surprising findings linking increased PI3K signaling to fast-flow arteriovenous malformations in hereditary hemorrhagic telangiectasias.

Introduction While hypercholesterolemia is a common feature of patients with type 2 diabetes (T2D), its role in the pathogenesis of this disease is not well established. The negative impact of [...], BACKGROUND. Preclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN)--suggestive of cellular cholesterol accumulation--were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation. METHODS. Monocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples. RESULTS. During a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes--ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression)--and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D. CONCLUSION. These data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis. FUNDING. The MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962.

Introduction The NOTCH3 gene encodes a receptor that is predominantly expressed in mural cells--pericytes and smooth muscle cells (SMCs)--of small blood vessels and is critically involved in the maturation, function, [...], Loss of arterial smooth muscle cells (SMCs) and abnormal accumulation of the extracellular domain of the NOTCH3 receptor ([Notch3.sup.ECD]) are the 2 core features of CADASIL, a common cerebral small vessel disease caused by highly stereotyped dominant mutations in NOTCH3. Yet the relationship between NOTCH3 receptor activity, [Notch3.sup.ECD] accumulation, and arterial SMC loss has remained elusive, hampering the development of disease-modifying therapies. Using dedicated histopathological and multiscale imaging modalities, we could detect and quantify previously undetectable CADASIL-driven arterial SMC loss in the CNS of mice expressing the archetypal Arg169Cys mutation. We found that arterial pathology was more severe and [Notch3.sup.ECD] accumulation greater in transgenic mice overexpressing the mutation on a wild-type Notch3 background ([TgNotch3.sup.R169C]) than in knockin [Notch3.sup.R170C/R170C] mice expressing this mutation without a wild-type Notch3 copy. Notably, expression of Notch3-regulated genes was essentially unchanged in [TgNotch3.sup.R169C] arteries. We further showed that wild-type [Notch3.sup.ECD] coaggregated with mutant [Notch3.sup.ECD] and that elimination of 1 copy of wild-type Notch3 in [TgNotch3.sup.R169C] was sufficient to attenuate [Notch3.sup.ECD] accumulation and arterial pathology. These findings suggest that [Notch3.sup.ECD] accumulation, involving mutant and wild-type NOTCH3, is a major driver of arterial SMC loss in CADASIL, paving the way for NOTCH3- lowering therapeutic strategies.

Introduction Craniofacial anomalies, especially midline facial defects, are among the most common birth defects found in patient populations whose appearance are either associated with increased mortality or require lifelong treatment [...], Craniofacial anomalies, especially midline facial defects, are among the most common birth defects in patients and are associated with increased mortality or require lifelong treatment. During mammalian embryogenesis, specific instructions arising at genetic, signaling, and metabolic levels are important for stem cell behaviors and fate determination, but how these functionally relevant mechanisms are coordinated to regulate craniofacial morphogenesis remain unknown. Here, we report that bone morphogenetic protein (BMP) signaling in cranial neural crest cells (CNCCs) is critical for glycolytic lactate production and subsequent epigenetic histone lactylation, thereby dictating craniofacial morphogenesis. Elevated BMP signaling in CNCCs through constitutively activated ACVR1 (ca-ACVR1) suppressed glycolytic activity and blocked lactate production via a p53- dependent process that resulted in severe midline facial defects. By modulating epigenetic remodeling, BMP signaling- dependent lactate generation drove histone lactylation levels to alter essential genes of Pdgfra, thus regulating CNCC behavior in vitro as well as in vivo. These findings define an axis wherein BMP signaling controls a metabolic/epigenetic cascade to direct craniofacial morphogenesis, thus providing a conceptual framework for understanding the interaction between genetic and metabolic cues operative during embryonic development. These findings indicate potential preventive strategies of congenital craniofacial birth defects via modulating metabolic-driven histone lactylation.

Lesion mimic mutants (LMMs) often display hypersensitive response-like (HR-like) cell death and enhanced resistance to pathogens. LMMs have heen viewed as useful for the study of the mechanism of cell death and plant immunity. To date, few LMMs have heen found in woody plants. We previously identified an LMM termed Imd, which showed spontaneous cell death in hirch. In the current study, we investigated Imd, oe21 (transgenic control), and NT (nontransgenic control), focusing on cell death and gene expression profile of Imd. We found that cell death in the Imd occurred gradually during leaf development. The number of necrotic spots increased as the leaf developed, with no significant change in spot size. Subcellular observations showed degradation of both mitochondria and chloroplasts in Imd cells but not in NT and oe21 cells. Autophagosomes were visible in dying cells of Imd. We then performed RNA-seq of the four most apical leaves of Imd and oe21 to explore the gene expression profile during cell death. Genes that were functional in signal perception, respiratory burst, signal transduction, and defense were enriched. TGA1, WRKY33, WRKY40, Chitinase, FLS2, RbohA/D, and SBT were identified as key genes involved in cell death in Imd. Key words: birch, cell death, defense, lesion mimic mutant, transcriptome Les mutants mimetiques d'une lesion (LMM) presentent souvent une mort cellulaire de type reponse hypersensible (HR) et une resistance accrue aux agents pathogenes. Les LMM ont ete considered comme utiles pour 1'etude des mecanismes de mort cellulaire et d'immunite chez les plantes. Jusqu'a present, peu de LMM ont ete decouverts chez les plantes ligneuses. Les auteurs ont precedemment identifie un LMM appele Imd, qui presentait une mort cellulaire spontanee chez le bouleau. Dans la presente etude, ils ont etudie Imd, oe21 (controle transgenique) et NT (controle non transgenique), en se concentrant sur la mort cellulaire et le profil d'expression genetique de Imd. Ils ont constate que la mort cellulaire de Imd se produisait progressivement au cours du developpement foliaire. Le nombre de taches necrotiques augmentait au cours du developpement foliaire, sans changement significatif de la taille des taches. Les observations subcellulaires montraient une degradation des mitochondries et des chloroplastes dans les cellules Imd contrairement aux cellules NT et oe21. Des autophagosomes etaient visibles dans les cellules Imd moribondes. Ils ont par la suite realise un sequencage de 1ARN des quatre feuilles les plus apicales de Imd et oe21 arm d'explorer le profil d'expression des genes pendant la mort cellulaire. Les genes qui etaient fonctionnels dans la perception des signaux, l'explosion respiratoire, la transduction des signaux et la defense etaient enrichis. TGA1, WKKY33, WRKY40, Chitinase, FLS2, EbohA/D et SBT ont ete identifies comme des genes cles impliques dans la mort cellulaire chez Imd. [Traduit par la Redaction] Mots-cles : bouleau, mort cellulaire, defense, mutant mimetique d'une lesion, transcriptome, Introduction Programmed cell death (PCD) occurs during all growth and developmental stages in plants including anther development, cell division, leaf morphogenesis, and senescence; this process is also known as developmentally [...]

Introduction Obesity has gradually become the focus of attention, which is characterized by energy imbalance and excessive accumulation of adipose tissue (Haslam and James 2005; Basham and Luik 2008). Its [...], The highly regulated proliferation of adipocytes plays a momentous role in fat development and obesity. Hoxa5 is an important member of the Hox family, its encoded protein is an important transcription factor related to development, and its differential expression in different adipose tissues seems to indicate that Hoxa5 may be involved in the regulation of adipocyte proliferation. To evaluate the regulatory mechanism of Hoxa5 on adipocyte proliferation, we constructed a variety of Hoxa5 expression vectors in vivo and in vitro to explore its mechanism on adipocyte proliferation and its potential impact on obesity. We observed that the overexpression of Hoxa5 strongly reduces cell counts and Hoxa5 can inhibit cell proliferation and block cell cycle progression by regulating the expression of genes such as Cyclin E, Cyclin Dl, and p53. Most importantly, we demonstrated that Hoxa5 exerts its effect by regulating the signaling pathway of Janus kinase 2 (JAK2) signal transduction and transcription 3 (STAT3) activator, as well as binding to the promoter region of Ccnel and inhibiting the transcription of Ccnel. This study provides an in-depth understanding of the potential molecular mechanism of Hoxa5 inhibiting adipocyte proliferation. Our results suggest the importance of Hoxa5 in the treatment of obesity. Key words: Hoxa5, adipose, cell cycle, Ccnel, JAK2/STAT3 pathway La proliferation hautement regulee des adipocytes joue un role cle dans le developpement du tissu graisseux et l'obesite. Hoxa5 est un membre important de la famille Hox, la proteine qu'il code etant un facteur de transcription important lie au developpement. Son expression differentielle dans differents types de tissus adipeux semble indiquer que Hoxa5 pourrait etre implique dans la regulation de la proliferation des adipocytes. Afin d'evaluer le mecanisme de regulation de Hoxa5 sur la proliferation des adipocytes, les auteurs ont construit une variete de vecteurs d'expression de Hoxa5 in vivo et in vitro pour explorer son mecanisme sur la proliferation des adipocytes et son impact potentiel sur l'obesite. Ils observe que la surexpression de Hoxa5 reduit fortement le nombre de cellules, et que Hoxa5 peut inhiber la proliferation cellulaire et bloquer la progression du cycle cellulaire en regulant l'expression de genes tels cycline E, cycline Dl etp53. Qui plus est, ils ont demontre que Hoxa5 exerce son effet en regulant la voie de signalisation de la Janus kinase 2 (JAK2) et de l'activateur de la transduction du signal et de la transcription 3 (STAT3), ainsi qu'en se liant a la region promotrice de Ccnel et en inhibant la transcription de Ccnel. Cette etude permet de comprendre de maniere approfondie le mecanisme moleculaire potentiel de Hoxa5 dans l'inhibition la proliferation des adipocytes. Ces resultats suggerent l'importance de Hoxa5 dans le traitement de l'obesite. [Traduit par la Redaction] Mots-cles : Hoxa5, adipeux, cycle cellulaire, Ccnel, voie JAK2/STAT3