Networks of sensors placed on the skin can provide continuous measurement of human physiological signals for applications in clinical diagnostics, athletics and human-machine interfaces. Wireless and ...battery-free sensors are particularly desirable for reliable long-term monitoring, but current approaches for achieving this mode of operation rely on near-field technologies that require close proximity (at most a few centimetres) between each sensor and a wireless readout device. Here, we report near-field-enabled clothing capable of establishing wireless power and data connectivity between multiple distant points around the body to create a network of battery-free sensors interconnected by proximity to functional textile patterns. Using computer-controlled embroidery of conductive threads, we integrate clothing with near-field-responsive patterns that are completely fabric-based and free of fragile silicon components. We demonstrate the utility of the networked system for real-time, multi-node measurement of spinal posture as well as continuous sensing of temperature and gait during exercise.
Electronic textiles capable of sensing, powering, and communication can be used to non-intrusively monitor human health during daily life. However, achieving these functionalities with clothing is ...challenging because of limitations in the electronic performance, flexibility and robustness of the underlying materials, which must endure repeated mechanical, thermal and chemical stresses during daily use. Here, we demonstrate electronic textile systems with functionalities in near-field powering and communication created by digital embroidery of liquid metal fibers. Owing to the unique electrical and mechanical properties of the liquid metal fibers, these electronic textiles can conform to body surfaces and establish robust wireless connectivity with nearby wearable or implantable devices, even during strenuous exercise. By transferring optimized electromagnetic patterns onto clothing in this way, we demonstrate a washable electronic shirt that can be wirelessly powered by a smartphone and continuously monitor axillary temperature without interfering with daily activities.
Energy release from cellular storage is mandatory for survival during fasting. This is achieved through lipolysis and liver gluconeogenesis. We show here that in the mouse, gut-derived serotonin ...(GDS) is upregulated during fasting and that it favors both mechanisms. In adipocytes, GDS signals through the Htr2b receptor to favor lipolysis by increasing phosphorylation and activity of hormone-sensitive lipase. In hepatocytes, GDS signaling through Htr2b promotes gluconeogenesis by enhancing activity of two rate-limiting gluconeogenic enzymes, FBPase and G6Pase. In addition, GDS signaling in hepatocytes prevents glucose uptake in a Glut2-dependent manner, thereby further favoring maintenance of blood glucose levels. As a result, inhibition of GDS synthesis can improve glucose intolerance caused by high-fat diet. Hence, GDS opposes deleterious consequences of food deprivation by favoring lipolysis and liver gluconeogenesis while preventing glucose uptake by hepatocytes. As a result, pharmacological inhibition of its synthesis may contribute to improve type 2 diabetes.
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▸ Gut-derived serotonin (GDS) synthesis is increased by fasting ▸ GDS enhances lipolysis by signaling in adipocytes through Htr2b receptor ▸ GDS favors gluconeogenesis and suppresses glucose uptake in liver by acting on Htr2b ▸ Inhibition of GDS synthesis ameliorates hyperglycemia in type 2 diabetes
The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms ...underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E
(PGE
), which stimulates β-catenin activation of GSC and M2-like TAM polarization. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE
production. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients.
Sequence alterations in microsatellites and an elevated mutational burden are observed in 20% of gastric cancers and associated with clinical response to anti-PD-1 antibodies. However, 50% of ...microsatellite instability-high (MSI-H) cancers are intrinsically resistant to PD-1 therapies. We conducted a phase II trial of pembrolizumab in patients with advanced MSI-H gastric cancer and included serial and multi-region tissue samples in addition to serial peripheral blood analyses. The number of whole-exome sequencing (WES)-derived nonsynonymous mutations correlated with antitumor activity and prolonged progression-free survival (PFS). Coupling WES to single-cell RNA sequencing, we identified dynamic tumor evolution with greater on-treatment collapse of mutational architecture in responders. Diverse T-cell receptor repertoire was associated with longer PFS to pembrolizumab. In addition, an increase in PD-1
CD8
T cells correlated with durable clinical benefit. Our findings highlight the genomic, immunologic, and clinical outcome heterogeneity within MSI-H gastric cancer and may inform development of strategies to enhance responsiveness. SIGNIFICANCE: This study highlights response heterogeneity within MSI-H gastric cancer treated with pembrolizumab monotherapy and underscores the potential for extended baseline and early on-treatment biomarker analyses to identify responders. The observed markers of intrinsic resistance have implications for patient stratification to inform novel combinations among patients with intrinsically resistant features.
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The cJun NH2-terminal kinase (JNK) stress signaling pathway is implicated in the metabolic response to the consumption of a high-fat diet, including the development of obesity and insulin resistance. ...These metabolic adaptations involve altered liver function. Here, we demonstrate that hepatic JNK potently represses the nuclear hormone receptor peroxisome proliferator-activated receptor α (PPARα). Therefore, JNK causes decreased expression of PPARα target genes that increase fatty acid oxidation and ketogenesis and promote the development of insulin resistance. We show that the PPARα target gene fibroblast growth factor 21 (Fgf21) plays a key role in this response because disruption of the hepatic PPARα-FGF21 hormone axis suppresses the metabolic effects of JNK deficiency. This analysis identifies the hepatokine FGF21 as a critical mediator of JNK signaling in the liver.
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•The PPARα-FGF21 hormone axis promotes insulin sensitivity•Consumption of a high-fat diet activates JNK in the liver•Hepatic JNK represses PPARα and contributes to systemic insulin resistance
Consumption of a high-fat diet activates the protein kinases JNK1/JNK2 in the liver. Vernia et al. identify the PPARα-FGF21 axis as a key target for hepatic JNK signaling to promote systemic insulin resistance.
Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal ...phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages.
We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCO
TAMs induce a phenotypic shift towards mesenchymal cellular state of glioma stem cells, promoting both invasive and proliferative activities, as well as therapeutic resistance to irradiation. MARCO
TAMs also significantly accelerate tumor engraftment and growth in vivo. Moreover, both MA-TAM master regulators and their target genes are significantly correlated with poor clinical outcomes and are often associated with genomic aberrations in neurofibromin 1 (NF1) and phosphoinositide 3-kinases/mammalian target of rapamycin/Akt pathway (PI3K-mTOR-AKT)-related genes. We further demonstrate the origination of MA-TAMs from peripheral blood, as well as their potential association with tumor-induced polarization states and immunosuppressive environments.
Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for improving the effectiveness of GBM immunotherapy.
The cJun NH 2 -terminal kinase (JNK) signaling pathway contributes to inflammation and plays a key role in the metabolic response to obesity, including insulin resistance. Macrophages are implicated ...in this process. To test the role of JNK, we established mice with selective JNK deficiency in macrophages. We report that feeding a high-fat diet to control and JNK-deficient mice caused similar obesity, but only mice with JNK-deficient macrophages remained insulin-sensitive. The protection of mice with macrophage-specific JNK deficiency against insulin resistance was associated with reduced tissue infiltration by macrophages. Immunophenotyping demonstrated that JNK was required for pro-inflammatory macrophage polarization. These studies demonstrate that JNK in macrophages is required for the establishment of obesity-induced insulin resistance and inflammation.
Sclerostin has traditionally been thought of as a local inhibitor of bone acquisition that antagonizes the profound osteoanabolic capacity of activated Wnt/β-catenin signaling, but serum sclerostin ...levels in humans exhibit a correlation with impairments in several metabolic parameters. These data, together with the increased production of sclerostin in mouse models of type 2 diabetes, suggest an endocrine function. To determine whether sclerostin contributes to the coordination of whole-body metabolism, we examined body composition, glucose homeostasis, and fatty acid metabolism in Sost−/− mice as well as mice that overproduce sclerostin as a result of adeno-associated virus expression from the liver. Here, we show that in addition to dramatic increases in bone volume, Sost−/− mice exhibit a reduction in adipose tissue accumulation in association with increased insulin sensitivity. Sclerostin overproduction results in the opposite metabolic phenotype due to adipocyte hypertrophy. Additionally, Sost−/− mice and those administered a sclerostin-neutralizing antibody are resistant to obesogenic diet-induced disturbances in metabolism. This effect appears to be the result of sclerostin’s effects on Wnt signaling and metabolism in white adipose tissue. Since adipocytes do not produce sclerostin, these findings suggest an unexplored endocrine function for sclerostin that facilitates communication between the skeleton and adipose tissue.
Abstract
The prognostic and therapeutic relevance of molecular subtypes for the most aggressive isocitrate dehydrogenase 1/2 (
IDH
) wild-type glioblastoma (GBM) is currently limited due to high ...molecular heterogeneity of the tumors that impedes patient stratification. Here, we describe a distinct binary classification of
IDH
wild-type GBM tumors derived from a quantitative proteomic analysis of 39
IDH
wild-type GBMs as well as
IDH
mutant and low-grade glioma controls. Specifically, GBM proteomic cluster 1 (GPC1) tumors exhibit Warburg-like features, neural stem-cell markers, immune checkpoint ligands, and a poor prognostic biomarker, FKBP prolyl isomerase 9 (
FKBP9
). Meanwhile, GPC2 tumors show elevated oxidative phosphorylation-related proteins, differentiated oligodendrocyte and astrocyte markers, and a favorable prognostic biomarker, phosphoglycerate dehydrogenase (
PHGDH
). Integrating these proteomic features with the pharmacological profiles of matched patient-derived cells (PDCs) reveals that the mTORC1/2 dual inhibitor AZD2014 is cytotoxic to the poor prognostic PDCs. Our analyses will guide GBM prognosis and precision treatment strategies.
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