Hyeongseok Kim

Regulation of systemic energy homeostasis by serotonin in adipose tissues

Central serotonin (5-HT) is an anorexigenic neurotransmitter in the brain. However, accumulating evidence suggests peripheral 5-HT may affect organismal energy homeostasis. Here we show 5-HT regulates white and brown adipose tissue function. Pharmacological inhibition of 5-HT synthesis leads to inhibition of lipogenesis in epididymal white adipose tissue (WAT), induction of browning in inguinal WAT and activation of adaptive thermogenesis in brown adipose tissue (BAT). Mice with inducible Tph1 KO in adipose tissues exhibit a similar phenotype as mice in which 5-HT synthesis is inhibited pharmacologically, suggesting 5-HT has localized effects on adipose tissues. In addition, Htr3a KO mice exhibit increased energy expenditure and reduced weight gain when fed a high-fat diet. Treatment with an Htr2a antagonist reduces lipid accumulation in 3T3-L1 adipocytes. These data suggest important roles for adipocyte-derived 5-HT in controlling energy homeostasis.

Islet-like organoids derived from human pluripotent stem cells efficiently function in the glucose responsiveness in vitro and in vivo.

Insulin secretion is elaborately modulated in pancreatic ß cells within islets of three-dimensional (3D) structures. Using human pluripotent stem cells (hPSCs) to develop islet-like structures with insulin-producing ß cells for the treatment of diabetes is challenging. Here, we report that pancreatic islet-like clusters derived from hESCs are functionally capable of glucose-responsive insulin secretion as well as therapeutic effects. Pancreatic hormone-expressing endocrine cells (ECs) were differentiated from hESCs using a step-wise protocol. The hESC-derived ECs expressed pancreatic endocrine hormones, such as insulin, somatostatin, and pancreatic polypeptide. Notably, dissociated ECs autonomously aggregated to form islet-like, 3D structures of consistent sizes (100–150 μm in diameter). These EC clusters (ECCs) enhanced insulin secretion in response to glucose stimulus and potassium channel inhibition in vitro. Furthermore, ß cell-deficient mice transplanted with ECCs survived for more than 40 d while retaining a normal blood glucose level to some extent. The expression of pancreatic endocrine hormones was observed in tissues transplanted with ECCs. In addition, ECCs could be generated from human induced pluripotent stem cells. These results suggest that hPSC-derived, islet-like clusters may be alternative therapeutic cell sources for treating diabetes.

Ectopic serotonin production in β-cell specific transgenic mice

Genetically modified mice have been widely used in the field of β-cell research. However, analysis of results gathered using genetically modified organisms should be interpreted carefully as the results may be confounded by several factors. Here, we showed the ectopic serotonin (5-HT) production in β-cells of RIP-CreMgn, MIP-GFP, and MIP-Cre/ERT mice. These mice contained a human growth hormone (hGH) cassette to enhance transgene expression and hGH expression and Stat5 phosphorylation were detected in pancreatic islets of these mice. The expression level of tryptophan hydroxylase 1 (Tph1) was upregulated in pancreatic islets of transgenic mice with an hGH cassette but not in transgenic mice without an hGH cassette. Ectopic 5-HT production was not observed in β-cell-specific prolactin receptor (Prlr) knockout mice or Stat5 knockout mice crossed with RIP-CreMgn. We further confirmed that 5-HT production in β-cells of several transgenic mice was induced by hGH expression followed by the activation of the Prlr-Stat5-Tph1 pathway. These findings indicate that results obtained using transgenic mice containing the hGH cassette should be interpreted with care.

Inhibition of Serotonin Synthesis Induces Negative Hepatic Lipid Balance.

Background Hepatic steatosis is caused by metabolic stress associated with a positive lipid balance, such as insulin resistance and obesity. Previously we have shown the anti-obesity effects of inhibiting serotonin synthesis, which eventually improved insulin sensitivity and hepatic steatosis. However, it is not clear whether serotonin has direct effect on hepatic lipid accumulation. Here, we showed the possibility of direct action of serotonin on hepatic steatosis. Methods Mice were treated with para-chlorophenylalanine (PCPA) or LP-533401 to inhibit serotonin synthesis and fed with high fat diet (HFD) or high carbohydrate diet (HCD) to induce hepatic steatosis. Hepatic triglyceride content and gene expression profiles were analyzed. Results Pharmacological and genetic inhibition of serotonin synthesis reduced HFD-induced hepatic lipid accumulation. Furthermore, short-term PCPA treatment prevented HCD-induced hepatic steatosis without affecting glucose tolerance and browning of subcutaneous adipose tissue. Gene expression analysis revealed that the expressions of genes involved in de novo lipogenesis and triacylglycerol synthesis were downregulated by short-term PCPA treatment as well as long-term PCPA treatment. Conclusion Short-term inhibition of serotonin synthesis prevented hepatic lipid accumulation without affecting systemic insulin sensitivity and energy expenditure, suggesting the direct steatogenic effect of serotonin in liver.

A novel pre‐processing technique for improving image quality in digital breast tomosynthesis

Purpose: Nonlinear pre‐reconstruction processing of the projection data in computed tomography (CT) where accurate recovery of the CT numbers is important for diagnosis is usually discouraged, for such a processing would violate the physics of image formation in CT. However, one can devise a pre‐processing step to enhance detectability of lesions in digital breast tomosynthesis (DBT) where accurate recovery of the CT numbers is fundamentally impossible due to the incompleteness of the scanned data. Since the detection of lesions such as micro‐calcifications and mass in breasts is the purpose of using DBT, it is justified that a technique producing higher detectability of lesions is a virtue. Methods: A histogram modification technique was developed in the projection data domain. Histogram of raw projection data was first divided into two parts: One for the breast projection data and the other for background. Background pixel values were set to a single value that represents the boundary between breast and background. After that, both histogram parts were shifted by an appropriate amount of offset and the histogram‐modified projection data were log‐transformed. Filtered‐backprojection (FBP) algorithm was used for image reconstruction of DBT. To evaluate performance of the proposed method, we computed the detectability index for the reconstructed images from clinically acquired data. Results: Typical breast border enhancement artifacts were greatly suppressed and the detectability of calcifications and masses was increased by use of the proposed method. Compared to a global threshold‐based post‐reconstruction processing technique, the proposed method produced images of higher contrast without invoking additional image artifacts. Conclusions: In this work, we report a novel pre‐processing technique that improves detectability of lesions in DBT and has potential advantages over the global threshold‐based post‐reconstruction processing technique. The proposed method not only increased the lesion detectability but also reduced typical image artifacts pronounced in conventional FBP‐based DBT.

SU‐E‐T‐79: Fabrication of Miniature X‐Ray Tube Using Carbon Nanotube Field Emitter for Electronic Brachytherapy

Purpose: A miniature x‐ray tube with the diameter of 10 mm has been fabricated using a carbon nanotube(CNT)field emitter, optimal design of electron optics and x‐ray target, and vacuum sealing of the x‐ray tube. The CNT emitter with nm∼μm scale and simpler cathode structure was used for miniaturization of x‐ray tube. A truncated conical shaped beryllium (Be) and thin tungsten (W) coating were adopted to emit 3‐dimensionally uniform x‐ray as an isotropic radiation source. Anode grounded high voltage (HV) connection and vacuum sealed x‐ray tube structure within 10 mm diameter are advantages for intra‐cavitary or skin surface electronic brachytherapy. Methods: The miniature x‐ray tube consisted with a tip‐shaped CNT emitter with the diameter of 0.25∼0.8 mm, a focusing electrode, a transmission‐type x‐ray target, getter film and a metalized HV isolation ceramic. The CNT emitter has been fabricated by coating and sintering of CNT and Silver nano particle mixture on the flat W tip. The miniature x‐ray tube is brazed in a 3×10−6 torr of vacuum furnace. The electron and x‐ray emission are calculated by EGN2 and MCNP5 program, and measure using a precision current meter (Fluke multimeter 189), a soft x‐ray chamber (PTW 34013), and x‐ray spectrometer (Amptek XR‐100t‐CdTe). Results: The CNT emitter emitted electron current over 1 mA at −9.8 kV/5 mm, and 0.1 mA was continued for over 3000 minutes with decrease ratio of −0.01 μA/min. The diode‐type miniature x‐ray tube is started to emit less than 5 Gy/min x‐ray at cm air depth from −20 kV to −50 kV following the gate to CNTcathode gap, and applying cathode voltage. Conclusions: The miniature x‐ray tube using CNTfield emitter has been demonstrated. The CNT based x‐ray tube can be more miniature, and is expected to apply various field of electronic brachytherapy, soon. This work was supported by the R&D Program of MKE/KEIT (10035553, Development of multi‐direction X‐ray emitting super‐miniature X‐ray tube for intra‐cavity imaging system) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2010‐0020387).

Suspension of a field-cooled BiPbSrCaCuO high-Tc superconductor under a toroidal permanent magnet

Magnetic flux measurements of a toroidal magnet revealed a concave-shaped field distribution with a single minimum and a null field along the axis of the torus at the point where the field reversed. The non-linear magnetic field of the toroidal magnet perpendicular to the Ag2O-doped superconducting disc sample with trapped magnetic flux distorted the field line distribution. As a result, the interaction force between the magnet and the sample exhibited regions of repulsive, null, attractive, null and finally repulsive force. The asymmetrical concave-shaped force pattern along the axis with two null force points indicates that the force exerted on the sample changes direction, the transition from repulsive to attractive at the null force point, and the force becomes repulsive again beyond the second null force point as the distance along the axis increases. The magnetic field simulation using the Poisson numerical code for the toroidal magnet of 46 mm OD, 12 mm ID and 10 mm thickness was in close agreement with the force measurements. The lateral stability of a suspended sample under the toroidal magnet is provided by the characteristic symmetrical nature of the field line with respect to the axis of the magnet. The concave-shaped magnetic field forms a vertical magnetic wall around a suspended superconducting sample as demonstrated with lead, a type 1 superconductor. Thus, the toroidal magnet with a concave-shaped magnetic field distribution with respect to the mid-plane of the magnet provides much improved lateral stability for the magnetic bearing. Furthermore, this arrangement provides a loss-free shielding current in the absence of viscous drag from the environment or eddy current or hysteresis. The magnetic moment of an undoped and 2% Ag2O-doped samples was shown to be m = 0.043 emu and 0.06 emu, respectively. The measured suspension force exerted on the doped sample agreed well with that calculated from the magnetostatic force distribution.