Search

Medullary thyroid cancer originates from parafollicular C-cells in the thyroid. Despite successful thyroidectomy, localizing remnant cancer cells in patients with elevated calcitonin and carcinoembryonic antigen levels remains a challenge. Extranasal odorant receptors are expressed in cells from non-olfactory tissues, including C-cells. This study evaluates the odorant receptor signals from parafollicular C-cells, specifically, the presence of olfactory marker protein, and further assesses the ability of the protein in localizing and treating medullary thyroid cancer. We used immunohistochemistry, immunofluorescent staining, Western blot, RNA sequencing, and real time-PCR to analyze the expression of odorant receptors in mice thyroids, thyroid cancer cell lines, and patient specimens. We used in vivo assays to analyze acetate binding, calcitonin secretion, and cAMP pathway. We also used positron emission tomography (PET) to assess C11-acetate uptake in medullary thyroid cancer patients. We investigated olfactory marker protein expression in C-cells in patients and found that it co-localizes with calcitonin in C-cells from both normal and cancer cell lines. Specifically, we found that OR51E2 and OR51E1 were expressed in thyroid cancer cell lines and human medullary thyroid cancer cells. Furthermore, we found that in the C-cells, the binding of acetate to OR51E2 activates its migration into the nucleus, subsequently resulting in calcitonin secretion via the cAMP pathway. Finally, we found that C11-acetate, a positron emission tomography radiotracer analog for acetate, binds competitively to OR51E2. We confirmed C11-acetate uptake in cancer cells and in human patients using PET. We demonstrated that acetate binds to OR51E2 in C-cells. Using C11-acetate PET, we identified recurrence sites in post-operative medullary thyroid cancer patients. Therefore, OR51E2 may be a novel diagnostic and therapeutic target for medullary thyroid cancer.

An electrospun nanofiber membrane significantly improves the electrical performances of triboelectric nanogenerators (TENGs) due to its high surface area. In recent years, composite nanofibers were applied to a TENG using various electrospinning system types to further enhance the performance of TENGs; however, the effects of the systems on the energy harvesting capability of TENGs have not been investigated thoroughly. This study aims to fabricate polyimide/poly(vinylidene fluoride-co-trifluoroethylene) composite nanofiber-based TENGs with three different nozzle systems: single nozzle, conjugated nozzle, and multinozzles, and two different collectors: plate collector and drum collector. A TENG with multinozzle-drum system-based nanofibers produced an output voltage of 364 V, a short-circuit current of 17.2 μA, a transferred charge of 29.72 nC, and a power density of 2.56 W/m2 at a load resistance of 100 MΩ, which were ∼7 times higher than those of other system-based nanofibers. Under the 10,000 cycles of loading, the TENG stably harvested electric energy. The TENG could also harvest energy from the human body motions, and it is sufficient to illuminate 117 light-emitting diodes and drive several electronic devices. The proposed TENG exhibits excellent electric performances as a wearable energy harvester.

The liver is one of the most common sites of breast cancer metastasis and is associated with high lethality. Although the interaction between tumor cells and their microenvironment at metastatic sites has been recognized as a key regulator of tumor progression, the underlying mechanism is not fully elucidated. Here, we describe a three-dimensional (3D) microfluidic human liver-on-a-chip (liver-chip) that emulates the formation of a premetastatic niche to investigate the roles of breast cancer-derived extracellular vesicles (EVs) in liver metastasis. We demonstrate that breast cancer-derived EVs activate liver sinusoidal endothelial cells (LSECs) in the liver-chip, inducing endothelial to mesenchymal transition and destruction of vessel barriers. In addition, we show that transforming growth factor β1 (TGFβ1) in breast cancer-derived EVs upregulates fibronectin, an adhesive extracellular matrix protein, on LSECs, which facilitates the adhesion of breast cancer cells to the liver microenvironment. Furthermore, we observed that EVs isolated from triple-negative breast cancer (TNBC) patients with liver metastasis contain higher TGFβ1 levels and induce adhesion of more breast cancer cells to the 3D human liver-chip than do EVs isolated from healthy donors or nonmetastatic TNBC patients. These findings provide a better understanding of the mechanisms through which breast cancer-derived EVs guide secondary metastasis to the liver. Furthermore, the 3D human liver-chip described in this study provides a platform to investigate the mechanisms underlying secondary metastasis to the liver and possible therapeutic strategies.

INTRODUCTION: Adipose tissue and adipocytes are primary regulators of insulin sensitivity and energy homeostasis. Defects in insulin sensitivity of the adipocytes predispose the body to insulin resistance (IR) that could lead to diabetes. However, the mechanisms mediating adipocyte IR remain elusive, which emphasizes the need to develop experimental models that can validate the insulin signaling pathways and discover new mechanisms in the search for novel therapeutics. Currently in vitro adipose organ-chip devices show superior cell function over conventional cell culture. However, none of these models represent disease states. Only when these in vitro models can represent both healthy and disease states, they can be useful for developing therapeutics. Here, we establish an organ-on-chip model of insulin-resistant adipocytes, as well as characterization in terms of insulin signaling pathway and lipid metabolism. METHODS: We differentiated, maintained, and induced insulin resistance into primary adipocytes in a microfluidic organ-on-chip. We then characterized IR by looking at the insulin signaling pathway and lipid metabolism, and validated by studying a diabetic drug, rosiglitazone. RESULTS: We confirmed the presence of insulin resistance through reduction of Akt phosphorylation, Glut4 expression, Glut4 translocation and glucose uptake. We also confirmed defects of disrupted insulin signaling through reduction of lipid accumulation from fatty acid uptake and elevation of glycerol secretion. Testing with rosiglitazone showed a significant improvement in insulin sensitivity and fatty acid metabolism as suggested by previous reports. CONCLUSIONS: The adipose-chip exhibited key characteristics of IR and can serve as model to study diabetes and facilitate discovery of novel therapeutics. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12195-020-00636-x) contains supplementary material, which is available to authorized users.

This study proposes a grid-connected inverter for photovoltaic (PV)-powered electric vehicle (EV) charging stations. The significant function of the proposed inverter is to enhance the stability of a microgrid. The proposed inverter can stabilize its grid voltage and frequency by supplying or absorbing active or reactive power to or from a microgrid using EVs and PV generation. Moreover, the proposed inverter can automatically detect an abnormal condition of the grid, such as a blackout, and operate in the islanding mode, which can provide continuous power to local loads using EV vehicle-to-grid service and PV generation. These inverter functions can satisfy the requirements of the grid codes, such as IEEE Standard 1547–2018 and UL 1741 SA. In addition, the proposed inverter can not only enhance the microgrid stability but also charge EVs in an appropriate mode according to the condition of the PV array and EVs. The proposed inverter was verified through experimental results with four scenarios in a lab-scale testbed. These four scenarios include grid normal conditions, grid voltage fluctuations, grid frequency fluctuations, and a power blackout. The experimental results demonstrated that the proposed inverter could enhance the microgrid stability against grid abnormal conditions, fluctuations of grid frequency and voltage, and charge EVs in an appropriate mode.

Isle of Reflections is an interactive lighting installation that can only be remotely explored via videotelephony. Viewers visit the island filled with iridescent lights and colorful reflections through Zoom, a popular web-based video communication tool. When the viewers see the lights and shadows that respond immediately to their voice through the screen, they recognize that they are interacting with a distant physical space in real-time. The viewers move between "breakout rooms" in Zoom to explore this virtual island filled with an immersive spectrum of light and color. Each room provides live scenes of the island from different viewing angles.

Expression and function of odorant receptors (ORs), which account for more than 50% of G protein–coupled receptors, are being increasingly reported in nonolfactory sites. However, ORs that can be targeted by drugs to treat diseases remain poorly identified. Tumor-derived lactate plays a crucial role in multiple signaling pathways leading to generation of tumor-associated macrophages (TAMs). In this study, we hypothesized that the macrophage OR Olfr78 functions as a lactate sensor and shapes the macrophage–tumor axis. Using Olfr78(+/+) and Olfr78(−/−) bone marrow–derived macrophages with or without exogenous Olfr78 expression, we demonstrated that Olfr78 sensed tumor-derived lactate, which was the main factor in tumor-conditioned media responsible for generation of protumoral M2-TAMs. Olfr78 functioned together with Gpr132 to mediate lactate-induced generation of protumoral M2-TAMs. In addition, syngeneic Olfr78-deficient mice exhibited reduced tumor progression and metastasis together with an increased anti- versus protumoral immune cell population. We propose that the Olfr78–lactate interaction is a therapeutic target to reduce and prevent tumor progression and metastasis.

Cysteamine (CA) is a cystine depleting agent used in the treatment of cystinosis and many other diseases. However, high dose of CA can be toxic and thus point-of-care-test devices measuring blood CA level can be highly beneficial. Here, we report a highly sensitive, straightforward, and quantitative assay for the colorimetric and spectroscopic determination of CA concentration using plasmonic nanoparticles. The principle is based on the chemical etching-induced exchange of the surface ligands of plasmonic gold nanoparticles (AuNPs) upon the addition of CA. Moreover, destabilized particles can aggregate to generate the plasmonic couplings that trigger the redshift in the ultraviolet-visible (UV-vis) spectrum (the absorption band shifted from 526 to 732 nm) and the solution color change (wine-red to blackish-blue). This plasmonic AuNPs sensor displays a clear red-to-blue colorimetric transition in the presence of CA among various biothiols with high specificity and sensitivity within a short time (15 s). Furthermore, a lab-on-a-disc platform was applied to the analysis of blood samples donated by healthy volunteers spiked with known amounts of the CA standard solution. This fully automated lab-on-a-disc platform approach for naked eye detecting the CA concentration in human blood samples (20 μL) is highly simple and time-efficient (6 min), and it would be potentially useful for the careful selection of CA doses in the hospital industry.

Indolocarbazole-Pyridine (IP) hybrid foldamers have been known to adopt a helical conformation with an internal tubular cavity wherein water molecules are tightly packed via the formation of multiple cooperative hydrogen bonds. In order to develop IP foldamer-based receptors for ions and molecules other than water molecules, we herein prepare two modified IP foldamers 2 and 3 that contain a pyrrole and an inverted pyridine in the middle of the strands, respectively, instead of the original pyridine unit. Such site-specific modification significantly disrupts the hydrogen-bonding network between the entrapped water molecules and the interior of the cavity, thus allowing for binding two dihydrogenphosphate ions as a cyclic dimer inside the cavity as demonstrated by 1H NMR spectroscopy and X-ray crystal structure analysis. The crystal structures of the two complexes (H2PO4−)2 ⊂ 2 and (H2PO4−)2 ⊂ 3 are very similar to each other, with twelve hydrogen bonds between the bound dihydrogenphosphate dimer and the interior functional groups, indolocarbazole NH protons, pyridine nitrogen atoms and terminal OH protons in the helical tubular cavity.

Doping heteroatoms such as nitrogen (N) and boron (B) into the framework of carbon materials is one of the most efficient methods to improve the electrical performance of carbon-based electrodes. In this study, N-doped carbon has been facilely synthesized using a ZIF-8/polydopamine precursor. The polyhedral structure of ZIF-8 and the effective surface-coating capability of dopamine enabled the formation of N-doped carbon with a hollow structure. The ZIF-8 polyhedron served as a sacrificial template for hollow structures, and dopamine participated as a donor of the nitrogen element. When compared to ZIF-8-derived carbon, the HSNC electrode showed an improved reversible capacity of approximately 1398 mAh·g−1 after 100 cycles, with excellent cycling retention at a voltage range of 0.01 to 3.0 V using a current density of 0.1 A·g−1.

Simple Summary Considering the spatiotemporal heterogeneity, more frequent monitoring of the disease progress using less-invasive liquid biopsy technologies is highly desired. Here, we demonstrate that epidermal growth factor receptor (EGFR) mutations could be readily detected from minimally invasive bronchial washing (BW)-derived EVs with good accuracy. The acquisition of T790M resistance mutation was detected earlier in BW-derived EVs than in plasma or tissue samples. The longitudinal analysis of BW-derived EVs showed excellent correlation with the disease progression measured by CT images. We demonstrate the clinical potential of BW-derived EVs as a liquid-biopsy sample for prognosis and precision medicine in patients with lung cancer. Abstract The detection of epidermal growth factor receptor (EGFR) mutation, based on tissue biopsy samples, provides a valuable guideline for the prognosis and precision medicine in patients with lung cancer. In this study, we aimed to examine minimally invasive bronchial washing (BW)-derived extracellular vesicles (EVs) for EGFR mutation analysis in patients with lung cancer. A lab-on-a-disc equipped with a filter with 20-nm pore diameter, Exo-Disc, was used to enrich EVs in BW samples. The overall detection sensitivity of EGFR mutations in 55 BW-derived samples was 89.7% and 31.0% for EV-derived DNA (EV-DNA) and EV-excluded cell free-DNA (EV-X-cfDNA), respectively, with 100% specificity. The detection rate of T790M in 13 matched samples was 61.5%, 10.0%, and 30.8% from BW-derived EV-DNA, plasma-derived cfDNA, and tissue samples, respectively. The acquisition of T790M resistance mutation was detected earlier in BW-derived EVs than plasma or tissue samples. The longitudinal analysis of BW-derived EVs showed excellent correlation with the disease progression measured by CT images. The EGFR mutations can be readily detected in BW-derived EVs, which demonstrates their clinical potential as a liquid-biopsy sample that may aid precise management, including assessment of the treatment response and drug resistance in patients with lung cancer.

Many museums have begun to use mobile devices to provide interactive content to visitors. However, such devices can also easily distract visitors, drawing their attention away from the exhibits. In this pictorial, we show the steps in designing Scienscope-a hand-held mediation device that can be used as a stethoscope to explore additional information hidden within exhibits at close range. As Scienscope hovers on authentic objects, it provides digital content and audio-haptic feedback, reinforcing the visitors' exploratory behaviors. After interviewing museum experts and bodystorming the museum space, we followed an iterative design process using low-fi prototyping to explore the users' experience. Three application scenarios were devised to show how Scienscope can be used for different types of exhibits. We discussed how visitors respond to and explore hidden information about exhibits at close range, which can be helpful for museum curators and designers.

The development of insulin resistance (IR) in liver is a key of pathophysiologic response in type 2 diabetes. Although insulin resistance impairs its ability to suppress hepatic glucose production, insulin regulation of lipogenesis is maintained (1). Currently available insulin sensitizers are effective at lowering glucose levels, but have significant adverse effect on weight gain due to triglyceride accumulation, which highlights a need to develop new therapeutic treatment options for type 2 diabetes. Brown adipose tissue (BAT) has been studied as a new target for anti-obesity and type 2 diabetes as BAT stimulation increases energy expenditure, reduces adiposity, and improves insulin sensitivity (2). However, the underlying mechanisms are not completely understood. To identify the role of BAT adipokines on hepatic insulin resistance, we developed an insulin resistant liver organ-on-chip model and then perfused primary mouse brown adipocyte conditioned media through the hepatocytes. Our results demonstrate that IR hepatocytes treated with brown adipocyte - conditioned media restores insulin sensitivity and improves glucose metabolism. This was verified by significantly increased expression of Phospho-Akt (Ser473) and glucose production gene markers (G6pc and PEPCK), lowered glucose production, increased glucose uptake, and increased glycogen synthesis in treated hepatocytes over IR group (p < 0.05). Our results also indicate that brown adipocyte - conditioned media treatment has the potential to suppress lipogenesis in hepatic insulin resistance. This was confirmed by significantly reduced expression of a lipogenesis gene marker (SREPB1) and fatty acid uptake in treated hepatocytes over IR group (p < 0.05). Current efforts are focused towards identifying the BAT adipokine via mass spectrometry. We conclude that BAT-derived endocrine factors could be a potential target for new drug discovery for obesity and type 2 diabetes treatment. Reference: (1) Langlet et al. Cell. 2017 Nov;171(4):824-835. (2) Subhadraw et al. Am J Physiol Endocrinol Metlab. 2015 Jun;308(12):E1043-E1055. Nothing to Disclose: NT, CL, AT, FZ, KK, JM, RC, AB

Puppet Book is a new concept of a digital storybook that is incorporated with puppetry. It enables parents to manipulate characters in real-time through a back-of-device interface while reading a storybook to their children. Puppet Book aims to provide enhanced expressiveness for parents and immersion for children. The Puppet Book interface was implemented carefully to minimize parents' task workload and maximize the expressiveness of puppeteering. A user study with 11 parent-child groups was conducted. Parents who easily adapted to the interface showed a higher motivation to tell the story, by identifying themselves with the characters. Children showed increased concentration and motivation for reading.

Tumor-derived extracellular vesicles (EVs) have emerged as a promising source of circulating biomarkers for liquid biopsies. However, understanding the heterogeneous physical and biochemical properties of EVs originating from multiple complex biogenesis pathways remains a major challenge. Here, we introduce EV-Ident for preparation of subpopulations of EVs in three different size fractions: large EVs (EV

The development of hepatic insulin resistance (IR) is a critical factor in developing type 2 diabetes (T2D), where insulin fails to inhibit hepatic glucose production but retains its capacity to promote hepatic de novo lipogenesis leading to hyperglycemia and hypertriglyceridemia. Improving insulin sensitivity can be effective in preventing and treating T2D. However, selective control of glucose and lipid synthesis has been difficult. It is known that excess white adipose tissue is detrimental to insulin sensitivity, whereas brown adipose tissue transplantation can restore it in diabetic mice. However, challenges remain in our understanding of liver-adipose communication because the confounding effects of hypothalamic regulation of metabolic function cannot be ruled out in previous studies. There is a lack of in vitro models that use primary cells to study cellular-crosstalk under insulin resistant conditions. Building upon our previous work on the microfluidic primary liver and adipose organ-on-chips, we report for the first time, the development of an integrated insulin resistant liver-adipose (white and brown) organ-on-chip. The design of the microfluidic device was carried out using computational fluid dynamics; the experimental studies were conducted by carrying out detailed biochemical analysis RNA-seq analysis on both cell types. Further, we tested the hypothesis that brown adipocytes (BAC) regulated both hepatic insulin sensitivity and de novo lipogenesis. Our results show that BAC effectively restored insulin sensitivity and supressed hepatic glucose production and de novo lipogenesis suggesting that the experimental platform could be useful for identifying potential therapeutics to treat IR and diabetes.

The use of microfluidics has become widespread in recent years because of the use of lesser resources such as small size, low volume of reagents, and physiological representation of mammalian cells. One of the advantages of microfluidic-based cell culture is the ability to perfuse culture media which tends to improve cellular health and function. Although measurement of cellular function conventionally is carried out using well-plates and plate readers, these approaches are insufficient to carry out in-line analysis of perfused cell cultures because of mismatch between volumes and sensitivity. We report the development of a novel microfluidic device and assay that is carried out under perfusion, in-line to measure the cholesterol secreted from a human hepatocyte tissue-chip. The heart of the assay is the unique implementation of enzymatic chemistry that is carried out on a polystyrene bead. Using this approach, we successfully measured cholesterol secreted by the perfused human hepatocytes.

Microglia (MG), the principal neuroimmune sentinels in the brain, continuously sense changes in their environment and respond to invading pathogens, toxins, and cellular debris, thereby affecting neuroinflammation. Microbial pathogens produce small metabolites that influence neuroinflammation, but the molecular mechanisms that determine whether pathogen-derived small metabolites affect microglial activation of neuroinflammation remain to be elucidated. We hypothesized that odorant receptors (ORs), the largest subfamily of G protein-coupled receptors, are involved in microglial activation by pathogen-derived small metabolites. We found that MG express high levels of two mouse ORs, Olfr110 and Olfr111, which recognize a pathogenic metabolite, 2-pentylfuran, secreted by Streptococcus pneumoniae. These interactions activate MG to engage in chemotaxis, cytokine production, phagocytosis, and reactive oxygen species generation. These effects were mediated through the Gαs -cyclic adenosine monophosphate-protein kinase A-extracellular signal-regulated kinase and Gβγ -phospholipase C-Ca2+ pathways. Taken together, our results reveal a novel interplay between the pathogen-derived metabolite and ORs, which has major implications for our understanding of microglial activation by pathogen recognition. DATABASE: Model data are available in the PMDB database under the accession number PM0082389.

Insulin resistance (IR) is a hallmark of T2D. In the IR state, insulin fails to inhibit hepatic glucose production yet promotes lipogenesis. Although thiazolidinediones can partially reinstate insulin sensitivity, there are concerns about long-term usage. Recent studies have shown positive effects of paracrine signaling from BAT transplant on metabolic homeostasis. Transplant of embryonic BAT into diabetic mice can improve glucose tolerance. However, the mechanisms are unclear. In this study, we show that brown adipocyte secretions can partially resolve hepatic IR. We cultured primary hepatocytes in a microfluidic organ-on-chip device. IR was induced by cytokine exposure and the cells were treated with brown adipocyte secretions among other controls. The group treated with brown adipocytes had restored insulin sensitivity. This was verified by an increased Akt phosphorylation (Figure 1), lowered glucose production, increased glucose uptake, and increased glycogen synthesis. We finally confirmed that genes important for glucose production (G6pc, PEPCK) and lipogenesis (SREBP1) were downregulated in the treated cells. We will present results from ongoing mechanistic studies. Our data imply that brown adipocyte secretions contain factors that regulate hepatic insulin sensitivity and could be potential targets for drug development. Disclosure A. Bhushan: None. N. Tanataweethum: None. C. Lee: None. F. Zhong: None. A. Trang: None. A. Budiman: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (DK095984NIH, P30DK020595)

Convolutional-Neural-Network (CNN) is used in broad applications. There are dataflows for convolutional layers in CNN such as row-stationary and weight-stationary. However, these dataflows have strengths and weaknesses. This paper analyzed two representative dataflows and introduce the dataflow-reconfigurable CNN accelerator that takes advantage of both dataflows.

In this study, we report an approach to achieve sequence-specific counting of single DNA molecules, which is required for more versatile applications of the previously reported absolute DNA quantification technique based on flow cytometric DNA single molecule counting. While using the same capillary-based flow cytometric setup, fluorescence activation of a target DNA was made with a number of fluorescent oligonucleotide probes of complementary sequences to that of a target DNA. The feasibility of the proposed approach was tested with 7 kb single-strand M13 DNA as the target DNA for sequence specific counting for quantification. Sample preparation, the number of fluorescent oligonucleotide probes, and hybridization conditions mainly matter for the performance of the proposed method. Using a set of 30 sequence-specific fluorescent probes with a selected hybridization buffer, acceptable performance was confirmed through comparison with other conventional methods such as digital polymerase chain reaction (dPCR), UV spectrophotometry, and deoxyribonucleoside monophosphate analysis by mass spectrometry. Proven comparability to the dPCR method confirmed the feasibility of the proposed approach. With further improvement in instrumentation, the proposed method is expected to become established as a reference measurement procedure for sequence-specific quantification of nucleic acids working under a uniquely straightforward measurement principle.

Background Rice cookers are one of home the appliances symbolizing the food culture of Korea. The shape of a rice cooker in the 1960s was different from the shape of a present one. With the growth of Korean society in the 1970s, rice cooker design began to change. The changes in rice cooker designs reflected the social and cultural tendencies of those times. This study aims to analyze the stream of Korean rice cooker designs from the 1970s to the 1990s and the social and cultural factors influencing the changes in designs. Methods In this study, the changes in rice cooker designs in 81 rice cooker advertisements in The Kyunghyang newspaper from the 1970s to the 1990s were considered and the social and cultural factors were analyzed, based on three standards; shape, pattern and color. Results In the 1970s, an electric rice cooker, which copied a Japanese rice cooker, appeared. But the rice cooked in the electric rice cooker was not good and people preferred rice cooked in an iron pot. For this reason, a high-pressure rice cooker that applied the shape and principle of an iron pot, appeared. But the high-pressure rice cooker did not keep rice warm. To remedy this, a ’heat-retaining rice cooker’ appeared in the 1980s. In the 1990s, the electric rice cooker became similar to the shape of a modern electric rice cooker and patterns or colors began to be applied to the appearance. There are five social and cultural factors, that influenced the changes in rice cooker designs from the 1970s to the 1990s. First, the shapes and materials of the rice cookers changed due to the emergence of a western-style stand-up kitchen. Second, with the introduction of KSmark, the shapes of rice cookers became fixed and standardized. Third, the quality of domestic rice cookers improved by copying Japanese rice cookers in the 1980s, but they failed to create their own unique designs. Fourth, with the emergence of color television, the outside colors of rice cookers were diversified. Fifth, women’s economic power increased and companies reflected female tastes in rice cooker designs more actively. Conclusions From the 1970s to the 1990s, which saw the upheaval of Korean society, rice cooker designs changed by being influenced by a variety of social and cultural factors of those times.