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The pleiotropic actions of the Farnesoid X Receptor (FXR) are required for gut health, and reciprocally, reduced intestinal FXR signaling is seen in inflammatory bowel diseases (IBDs). Here, we show that activation of FXR selectively in the intestine is protective in inflammation-driven models of IBD. Prophylactic activation of FXR restored homeostatic levels of pro-inflammatory cytokines, most notably IL17. Importantly, these changes were attributed to FXR regulation of innate lymphoid cells (ILCs), with both the inflammation-driven increases in ILCs, and ILC3s in particular, and the induction of Il17a and Il17f in ILC3s blocked by FXR activation. Moreover, a population of ILC precursor-like cells increased with treatment, implicating FXR in the maturation/differentiation of ILC precursors. These findings identify FXR as an intrinsic regulator of intestinal ILCs and a potential therapeutic target in inflammatory intestinal diseases.

This paper proposes a 2.4-GHz pre-bias RF energy harvesting rectifier with -35-dBm sensitivity for self-powered chips of wireless sensor networks (WSNs) for Internet of Things (IoT) applications. For high sensitivity, a pre-bias topology is presented by designing pre-stage and drive-stage rectifiers separately with multiple antennas. The pre-stage and the bias circuit just provide a proper bias voltage without driving loads. At single drive-stage configuration, -35-dBm sensitivity can be achieved with 2.4-GHz RF input power, 10-MΩ output load and 0.5-V continuous output voltage. When an 1% duty-cycled operating mode is adopted, 25-μW power can be supplied intermittently with 0.5-V output voltage. This proposed circuit is designed in 0.18-μm standard CMOS process.

Liver fibrosis is characterized by the persistent deposition of extracellular matrix components by hepatic stellate cell (HSC)-derived myofibroblasts. It is the histological manifestation of progressive, but reversible wound-healing processes. An unabated fibrotic response results in chronic liver disease and cirrhosis, a pathological precursor of hepatocellular carcinoma. We report here that JQ1, a small molecule inhibitor of bromodomain-containing protein 4 (BRD4), a member of bromodomain and extraterminal (BET) proteins, abrogate cytokine-induced activation of HSCs. Cistromic analyses reveal that BRD4 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, where BRD4 is colocalized with profibrotic transcription factors. Furthermore, we show that JQ1 is not only protective, but can reverse the fibrotic response in carbon tetrachloride-induced fibrosis in mouse models. Our results implicate that BRD4 can act as a global genomic regulator to direct the fibrotic response through its coordinated regulation of myofibroblast transcription. This suggests BRD4 as a potential therapeutic target for patients with fibrotic complications.

Increased levels of intestinal bile acids (BAs) are a risk factor for colorectal cancer (CRC). Here we show that the convergence of dietary factors (high-fat diet) and dysregulated WNT signaling (APC mutation) alters BA profiles to drive malignant transformations in Lgr5-expressing (Lgr5(+)) cancer stem cells and promote an adenoma-to-adenocarcinoma progression. Mechanistically, we show that BAs that antagonize intestinal Farnesoid X receptor (FXR) function, including tauro-β-muricholic acid (T-βMCA) and deoxycholic acid (DCA), induce proliferation and DNA damage in Lgr5(+) cells. Conversely, selective activation of intestinal FXR can restrict abnormal Lgr5(+) cell growth and curtail CRC progression. This unexpected role for FXR in coordinating intestinal self-renewal with BA levels implicates FXR as a potential therapeutic target for CRC.

In this paper, we propose a 16 quadrature amplitude modulated (QAM) backscatter for self-powered chips with a symbol rate of 1 MHz and a 40 Mb/s bit rate in 2.4 GHz Internet of Things (IoT) system. A four-resistor array is implemented to shift amplitude and achieve quadrature amplitude shift keying (QASK). Transmission lines of four different lengths are applied to change backscattering phase and accomplish quadrature phase shift keying (QPSK). Jointly, by applying transmission lines of twelve lengths and resistors of three values, a 16 QAM backscatter is realized, which is compatible with extensive mainstream communication protocols. The whole system is off-chip, completely passive and low-cost, leading to an easy, economic and efficient communication within wireless sensor networks (WSNs).

Summary: PGC1α is a pleiotropic co-factor that affects angiogenesis, mitochondrial biogenesis, and oxidative muscle remodeling via its association with multiple transcription factors, including the master oxidative nuclear receptor ERRγ. To decipher their epistatic relationship, we explored ERRγ gain of function in muscle-specific PGC1α/β double-knockout (PKO) mice. ERRγ-driven transcriptional reprogramming largely rescues muscle damage and improves muscle function in PKO mice, inducing mitochondrial biogenesis, antioxidant defense, angiogenesis, and a glycolytic-to-oxidative fiber-type transformation independent of PGC1α/β. Furthermore, in combination with voluntary exercise, ERRγ gain of function largely restores mitochondrial energetic deficits in PKO muscle, resulting in a 5-fold increase in running performance. Thus, while PGC1s can interact with multiple transcription factors, these findings implicate ERRs as the major molecular target through which PGC1α/β regulates both innate and adaptive energy metabolism. : Fan et al. demonstrate that ERRγ improves mitochondrial energy metabolism in PGC1α/β-deficient muscle through its direct activation of target genes. Such ERRγ-induced effects are further boosted in combination with exercise training, suggesting ERRs are the major transcriptional modulator through which PGC1α/β regulates both innate and adaptive energy metabolism. Keywords: ERR, estrogen related receptor, PGC1, mitochondria, muscle, exercise, vasculature, fatty acid oxidation, glycolysis, muscle damage

Mass cytometry uniquely enables high-dimensional single-cell analysis of complex populations. This recently developed technology is based on inductively coupled time-of-flight mass spectrometry for multiplex proteomic analysis of more than 40 markers per cell. The ability to characterize the transcriptome is critical for the understanding of disease pathophysiology, medical diagnostics, and drug discovery. Current techniques allowing the in situ detection of transcripts in single cells are limited to a small number of simultaneous targets and are generally tedious and labor-intensive. In this report, we present the development of a multiplex method for targeted RNA detection by combining the mass cytometry and RNAscope® platforms. This novel assay, called Metal In Situ Hybridization (MISH), includes the hybridization of RNA-specific target probes followed by signal amplification achieved through a cascade of hybridization events, ending with the binding of amplifier-specific detector probes. The detector probes are tagged with isotopically pure metal atoms used for detection by mass cytometry. Proof-of-principle experiments show the simultaneous detection of three mRNA targets in Jurkat cells in suspension cell assay mode. The localization of transcripts was also investigated using the imaging mass cytometry platform in Jurkat and KG-1a cells. In addition, we optimized the antibody staining procedure to allow the co-detection of mRNA and cell surface markers. Our data demonstrate that MISH can be used to complement protein detection by mass cytometry as well as to investigate gene transcription and translation in single cells. © 2017 International Society for Advancement of Cytometry.

Management of energy stores is critical during endurance exercise, with a shift in substrate utilization from glucose towards fat being a hallmark of trained muscle. Here we show that this key metabolic adaptation is both dependent on muscle PPARδ and stimulated by PPARδ ligand. Furthermore, we find that muscle PPARδ expression positively correlates with endurance performance in BXD mouse reference populations. In addition to stimulating fatty acid metabolism in sedentary mice, PPARδ activation potently suppresses glucose catabolism and does so without affecting either muscle fiber type or mitochondrial content. By preserving systemic glucose levels PPARδ acts to delay the onset of hypoglycemia and extends running time by ~100 minutes in treated mice. Collectively, these results identify a bifurcated PPARδ program that underlies glucose sparing and highlight the potential of PPARδ-targeted exercise mimetics in the treatment of metabolic disease, dystrophies and unavoidably, the enhancement of athletic performance.

This paper presents a 7.9 fJ/conversion-step 10-bit 125 MS/s successive approximation register (SAR) analog-to-digital converter (ADC) on the basis of a monotonic capacitor switching procedure. Simplified power-efficient digital control logic, multi-layer sandwich capacitor structure and high-speed level-shift bootstrapped sampling-and-holding (S/H) blocks are employed to achieve high performance with low power consumption. The prototype is implemented in 55 nm standard CMOS process, occupying an active area of 0.18 mm × 0.20 mm. Post simulation results show that an SNDR of 54.01 dB and an ENOB of 8.7 bit can be achieved by consuming 0.41 mW of the ADC core from a 1.2 V supply, and a figure of merit (FOM) of 7.9 fJ/conversion-step.

This paper presents a temperature and supply voltage variation-tolerant CMOS relaxation oscillator which is suitable for ultra-low power systems. A low-power low-cost half-period pre-charge compensation scheme is proposed to eliminate influences of the delay of the comparator and the RS latch on the frequency stability of the relaxation oscillator. In a clock period consisting of four working stages including normal charge, discharge, pre-charge and hold stage, the threshold voltage of comparators is adjusted dynamically. A 32.7-kHz relaxation oscillator with the proposed half-period pre-charge compensation scheme is implemented in a TSMC 0.18-μm CMOS process, occupying a silicon area of 0.048 mm2. Simulation results show that the proposed relaxation oscillator consumes 51-nW at room temperature from 0.6-V power supply, and temperature stability of 43.1 ppm/°C from −55 °C to 125 °C and ±0.60% frequency variation with supply voltage from 0.5 V to 1.0 V are achieved.

This paper proposes a DC-DC buck converter with all-pass network based passive level shifter in 55nm standard CMOS process, for battery powered portable applications. In order to handle high battery voltages in this advanced standard CMOS process, a passive level shifter based on all-pass network is applied for gate oxide protection. Drain extension is proposed to obtain high breakdown voltage of active region. The proposed buck converter with the passive level shifter works in DCM operation as its load current varies from 0.1–10mA. The buck converter achieves a peak efficiency of 93.7% and 83.8% at 10mA load current, with a supply voltage of 1.8V and 3.7V, respectively.

When facing with the mid-air interactive tasks in a wide range, the laser spot motion sensing technique can be as a information input mode of human-computer interaction(HCI). This paper explores the use of optical mouse sensors for building a laser spot tracking system, which can be used as a motion-based HCI device. Our work is focused on the characterization of the laser speckle sensing by optical mouse sensors. Based on the laser speckle displacement measurement capability of optical mouse sensors, we demonstrate that the low-cost optical mouse sensor can be used to record the motion of laser spot as a precise, fast and compact sensing method. To make a prototype system for demonstration, we describe a kind of deployment method for building optical mouse sensor array and propose a weighted method to fuse the raw data of multi-optical mouse sensor array. In experimental testing, the ISO standard tests for HCI input device were used for evaluating the efficiency of HCI input by optical mouse sensor-based laser spot tracking. A paradigm that using laser pointer and our laser spot tracking system to complete the dynamic hand gesture recognition task is also given in this paper.

Recently, Optical-flow sensors commonly used as a PC input device have been explored in robot localization. One common difficulty is that ground-height variations in mobile robot moving can inevitably deteriorate the sensing performance of optical-flow sensors when used in a trivial fashion. In this paper, a novel deployment configuration is presented to build an optical-flow sensor array for robot localization, which is advantageous in the robustness to ground-height variation. In addition, the imaging capability of optical mouse sensors is exploited in developing a beacon based calibration approach for eliminating accumulative errors. The experimental results are reported to validate the proposed method.

Although the lung is a defining feature of air-breathing animals, the pathway controlling the formation of type I pneumocytes, the cells that mediate gas exchange, is poorly understood. In contrast, the glucocorticoid receptor and its cognate ligand have long been known to promote type II pneumocyte maturation; prenatal administration of glucocorticoids is commonly used to attenuate the severity of infant respiratory distress syndrome (RDS). Here we show that knock-in mutations of the nuclear co-repressor SMRT (silencing mediator of retinoid and thyroid hormone receptors) in C57BL/6 mice (SMRTmRID) produces a previously unidentified respiratory distress syndrome caused by prematurity of the type I pneumocyte. Though unresponsive to glucocorticoids, treatment with anti-thyroid hormone drugs (propylthiouracil or methimazole) completely rescues SMRT-induced RDS, suggesting an unrecognized and essential role for the thyroid hormone receptor (TR) in lung development. We show that TR and SMRT control type I pneumocyte differentiation through Klf2, which, in turn, seems to directly activate the type I pneumocyte gene program. Conversely, mice without lung Klf2 lack mature type I pneumocytes and die shortly after birth, closely recapitulating the SMRTmRID phenotype. These results identify TR as a second nuclear receptor involved in lung development, specifically type I pneumocyte differentiation, and suggest a possible new type of therapeutic option in the treatment of RDS that is unresponsive to glucocorticoids.

The tumor microenvironment plays multiple roles in tumor cell proliferation, differentiation, vascularity, and metastasis through tumor cell-stromal cell interactions. The molecular responses of tumor cells to drug treatment can modify or be modified by the molecular signaling in stromal cells. Therefore, understanding the molecular features of both tumor cells and the tumor microenvironment is crucial for understanding cancer biology and the discovery of targeted therapy. Patient-derived xenograft (PDX) tumor models contain human tumor cells growing in a mouse stromal environment and are widely used models for cancer research and drug discovery. In this study we have applied in situ hybridization to visualize gene expression in human tumor and mouse stroma by developing species-specific probes based on the RNAscope technology. Eight genes were selected for this study based on their roles in a wide range of human cancers: EGFR, ERBB2, FGF19, FGFR1, FGFR4, MET, PECAM1 and TGFB1. We designed human and mouse species-specific probes by targeting the most divergent regions ( In both CRC and liver cancer PDX tumors, human-specific probes detected strong expression of ERBB2, FGFR4, and MET in human tumor cells but no signals in mouse stromal cells. Conversely, the mouse-specific probes only detected expression of Erbb2, Fgfr4, and Met genes in mouse stromal cells. Notably, strong expression of several mouse genes, including Tgfb1, Fgfr1, Egfr, and Pecam1, were detected in the stroma surrounding the human tumor by mouse-specific probes while no human probe signals were detected in the same region. Human TGFB1, FGFR1, EGFR, and PECAM1 probes detected varied levels of gene expression in the human tumor cells from the same sample without cross-detection of the mouse ortholog sequences in the stromal region. We also observed extensive gene expression heterogeneity, both within the same tumor and between tumors. Heterogeneity of FGFR4 and FGF19 expression in the liver cancer model was particularly notable. Our results indicate that RNAscope, a single molecule RNA detection method can robustly detect the expression patterns of FGFR4-FGF19 in PDX tumors and can be utilized for selecting PDX models for mouse trials with therapeutic agents targeting FGFR4 signaling pathway. Overall the findings in this study demonstrate the successful use of RNAscope based in-situ hybridization to examine human tumor specific gene expression in mouse stromal environment in PDX animal models by visualizing gene expression in both the human tumor and mouse stroma with species-specific probes. As human tumor engrafts acquire mouse stromal cells during growth in the murine host, the method presented here will further enable the molecular dissection in PDX tumor models of tumor-host interactions involved in tumor growth, progression, and metastasis as well as responses to cancer drugs and development of drug resistance. Citation Format: Emily Park, Na Li, Katherine Ye, Mingxiao He, Mingxiao He, Zhifu Zhang, Hongzhe Sun, Xin Wang, Courtney Anderson, Yuling Luo, Zhenyu Gu, Xiao-Jun Ma. Dissecting molecular pathways in human tumor vs. mouse stromal environment in patient-derived cancer models. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B03.

The Fluidigm® CyTOF system is a mass cytometer that uniquely enables high-dimensional single-cell analysis of complex populations. Mass cytometry is based on inductively coupled plasma time-of-flight mass spectrometry used for multiplex proteomic analysis. In this approach, metal-conjugated affinity reagents are used to tag the components of cells. The cells are nebulized and sent to an argon plasma, ionizing the multi-atom metal tags, which are then analyzed by a time-of-flight mass spectrometer. Gene expression can be finely tuned through the synthesis of RNA and through the control of its stability and location. Misregulation of gene expression can have severe consequences, such as developmental disorders, cancer and autoimmune diseases. The ability to acquire complete spatial-temporal profiles of gene expression is therefore critical for the understanding of disease pathophysiology, medical diagnostics and drug discovery. In this presentation, we discuss the development of a multiplex method for targeted RNA detection using the Fluidigm CyTOF® and Advanced Cell Diagnostics RNAscope® platforms. This novel assay includes the hybridization of RNA-specific target probes, followed by signal amplification and ending with the binding of amplifier-specific metal-labelled probes. Presently, we are able to detect four different mRNA probes in a single-cell analysis setting. The detection of RNA is compatible with Fluidigm products such as Maxpar® antibodies. Future developments will include high-dimensional detection that enables researchers to investigate the simultaneous expression profile of RNA and protein across millions of cells.

Although feast and famine cycles illustrate that remodelling of adipose tissue in response to fluctuations in nutrient availability is essential for maintaining metabolic homeostasis, the underlying mechanisms remain poorly understood(1,2). Here we identify fibroblast growth factor 1 (FGF1) as a critical transducer in this process in mice, and link its regulation to the nuclear receptor PPAR gamma (peroxisome proliferator activated receptor gamma), which is the adipocyte master regulator and the target of the thiazolidinedione class of insulin sensitizing drugs(3-5). FGF1 is the prototype of the 22-member FGF family of proteins and has been implicated in a range of physiological processes, including development, wound healing and cardiovascular changes(6). Surprisingly, FGF1 knockout mice display no significant phenotype under standard laboratory conditions(7-9). We show that FGF1 is highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet. Further analysis of adipose depots in FGF1-deficient mice revealed multiple histopathologies in the vasculature network, an accentuated inflammatory response, aberrant adipocyte size distribution and ectopic expression of pancreatic lipases. On withdrawal of the high-fat diet, this inflamed adipose tissue fails to properly resolve, resulting in extensive fat necrosis. In terms of mechanisms, we show that adipose induction of FGF1 in the fed state is regulated by PPAR gamma acting through an evolutionarily conserved promoter proximal PPAR response element within the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse establishes the PPAR gamma-FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization.

Although feast and famine cycles illustrate that remodelling of adipose tissue in response to fluctuations in nutrient availability is essential for maintaining metabolic homeostasis, the underlying mechanisms remain poorly understood.