A novel hydroxyfuroic acid compound as an insulin receptor activator - structure and activity relationship of a prenylindole moiety to insulin receptor activation

<p>Abstract</p> <p>Background</p> <p>Diabetes Mellitus is a chronic disease and many patients of which require frequent subcutaneous insulin injection to maintain proper blood glucose levels. Due to the inconvenience of insulin administration, an orally active insulin replacement has long been a prime target for many pharmaceutical companies. Demethylasterriquinone (DMAQ) B1, extracted from tropical fungus, <it>Pseudomassaria </it>sp., has been reported to be an orally effective agent at lowering circulating glucose levels in diabetic (<it>db/db</it>) mice; however, the cytotoxicity associated with the quinone moiety has not been addressed thus far.</p> <p>Methods</p> <p>A series of hydroxyfuroic acid compounds were synthesized and tested for their efficacies at activating human insulin receptor. Cytotoxicity to Chinese hamster ovary cells, selectivities over insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), and fibroblast growth factor (FGF) receptors were examined in this study.</p> <p>Result and Conclusion</p> <p>This study reports a new non-quinone DMAQ B1 derivative, a hydroxyfuroic acid compound (D-410639), which is 128 fold less cytotoxic as DMAQ B1 and as potent as compound 2, a DMAQ B1 synthetic derivative from Merck, at activating human insulin receptor. D-410639 has little activation potential on IGF-1 receptor but is a moderate inhibitor to EGF receptor. Structure and activity relationship of the prenylindole moiety to insulin receptor activation is discussed.</p

Generative Adversarial Method Based on Neural Tangent Kernels

The recent development of Generative adversarial networks (GANs) has driven many computer vision applications. Despite the great synthesis quality, training GANs often confronts several issues, including non-convergence, mode collapse, and gradient vanishing. There exist several workarounds, for example, regularizing Lipschitz continuity and adopting Wasserstein distance. Although these methods can partially solve the problems, we argue that the problems are result from modeling the discriminator with deep neural networks. In this paper, we base on newly derived deep neural network theories called Neural Tangent Kernel (NTK) and propose a new generative algorithm called generative adversarial NTK (GA-NTK). The GA-NTK models the discriminator as a Gaussian Process (GP). With the help of the NTK theories, the training dynamics of GA-NTK can be described with a closed-form formula. To synthesize data with the closed-form formula, the objectives can be simplified into a single-level adversarial optimization problem. We conduct extensive experiments on real-world datasets, and the results show that GA-NTK can generate images comparable to those by GANs but is much easier to train under various conditions. We also study the current limitations of GA-NTK and propose some workarounds to make GA-NTK more practical

An Investigation of the Differential Expression of Her2/neu Gene Expression in Normal Oral Mucosa, Epithelial Dysplasia, and Oral Squamous Cell Carcinoma in Taiwan

BackgroundHer2/neu was thought to be a proto-oncogene with sequence homology to epidermal growth factor receptor (EGFR). Its overexpression was seen in many cancers and referred to regimens of anticancer therapy. The aim of this study was to investigate whether the abnormal expression existed in oral carcinogenesis.MethodsImmunohistochemistry (IHC) was used to detect Her2/neu expression in normal oral mucosa (NOM) (n = 20), oral precancerous lesions of epithelial dysplasia (ED) (n = 20), and oral squamous cell carcinoma (OSCC) (n = 30). The association of clinicopathologic covariates of areca use, tumor size, neck lymph node metastasis, differentiation and stages of cancer with the expression of Her2/neu was examined. The significance of Neu immunoreactivity in different groups or with different covariates was investigated using Fisher's exact test.ResultsHer2/neu immunoreactivity was very low with Her2/neu(+) in 10% (2/20) of NOM cases and in 25% (5/20) of ED cases, respectively. The Her2/neu expression was high in OSCC cases, with 40% (12/30) of Her2/neu(+) and 10% (3/30) of Her2/neu(++). Significant difference was observed between NOM/ED and OSCC cases (p < 0.05). All clinicopathologic covariates showed no significant relation to the expression of Her2/neu in OSCC cases.ConclusionThese findings suggested a dynamic change in Her2/neu expression during the development of OSCC. The overexpression of Her2/neu can be used as a marker in distinguishing NOM/ED from OSCC

Metrology Camera System of Prime Focus Spectrograph for Subaru Telescope

The Prime Focus Spectrograph (PFS) is a new optical/near-infrared multi-fiber spectrograph designed for the prime focus of the 8.2m Subaru telescope. PFS will cover a 1.3 degree diameter field with 2394 fibers to complement the imaging capabilities of Hyper SuprimeCam. To retain high throughput, the final positioning accuracy between the fibers and observing targets of PFS is required to be less than 10um. The metrology camera system (MCS) serves as the optical encoder of the fiber motors for the configuring of fibers. MCS provides the fiber positions within a 5um error over the 45 cm focal plane. The information from MCS will be fed into the fiber positioner control system for the closed loop control. MCS will be located at the Cassegrain focus of Subaru telescope in order to to cover the whole focal plane with one 50M pixel Canon CMOS camera. It is a 380mm Schmidt type telescope which generates a uniform spot size with a 10 micron FWHM across the field for reasonable sampling of PSF. Carbon fiber tubes are used to provide a stable structure over the operating conditions without focus adjustments. The CMOS sensor can be read in 0.8s to reduce the overhead for the fiber configuration. The positions of all fibers can be obtained within 0.5s after the readout of the frame. This enables the overall fiber configuration to be less than 2 minutes. MCS will be installed inside a standard Subaru Cassgrain Box. All components that generate heat are located inside a glycol cooled cabinet to reduce the possible image motion due to heat. The optics and camera for MCS have been delivered and tested. The mechanical parts and supporting structure are ready as of spring 2016. The integration of MCS will start in the summer of 2016.Comment: 11 pages, 15 figures. SPIE proceeding. arXiv admin note: text overlap with arXiv:1408.287

High levels of serum macrophage migration inhibitory factor and interleukin 10 are associated with a rapidly fatal outcome in patients with severe sepsis

SummaryObjectivesThe aim of this study was to delineate the association between high macrophage migration inhibitory factor (MIF) and interleukin 10 (IL-10) levels in the early phase of sepsis and rapidly fatal outcome.MethodsOne hundred and fifty-three adult subjects with the main diagnosis of severe sepsis (including septic shock) admitted directly from the emergency department of two tertiary medical centers and one regional teaching hospital between January 2009 and December 2011, were included prospectively. MIF and IL-10 levels were measured and outcomes were analyzed by Cox regression analysis according to the following outcomes: rapidly fatal outcome (RFO, death within 48h), late fatal outcome (LFO, death between 48h and 28 days), and survival at 28 days.ResultsAmong the three outcome groups, IL-10 levels were significantly higher in the RFO group (p < 0.001) and no significant differences were seen between the LFO and survivor groups. After Cox regression analysis, each incremental elevation of 1000 pg/ml in both IL-10 and MIF was independently associated with RFO in patients with severe sepsis. Each incremental elevation of 1000 pg/ml in IL-10 increased the RFO risk by a factor of 1.312 (95% confidence interval 1.094–1.575; p=0.003); this was the most significant factor leading to RFO in patients with severe sepsis.ConclusionsPatients with RFO exhibited simultaneously high MIF and IL-10 levels in the early phase of severe sepsis. Incremental increases in both IL-10 and MIF levels were associated with RFO in this patient group, and of the two, IL-10 was the most significant factor linked to RFO

Prime Focus Spectrograph (PFS): the metrology camera system

The Prime Focus Spectrograph (PFS) is a new optical/near-infrared multi-fiber spectrograph designed for the prime focus of the 8.2m Subaru telescope. PFS will cover a 1.3 degree diameter field with 2394 fibers to complement the imaging capabilities of Hyper SuprimeCam. To retain high throughput, the final positioning accuracy between the fibers and observing targets of PFS is required to be less than 10 µ m. The metrology camera system (MCS) serves as the optical encoder of the fiber positioners for configuring of fibers. The MCS locates at the Cassegrain focus of the Subaru telescope to cover the whole focal plane with one 50M pixel CMOS sensor. The information from MCS will be fed into the fiber positioner control system for closed loop control. The MCS was delivered to Subaru Observatory in Apr. 2018 and it had two engineering runs in Oct. 2018 and Aug. 2019. The 1st engineering run concluded that the original mirror supports need to be improved to provide better image quality. The newly designed mirror supports were installed before the 2nd engineering run. The 2nd engineering run result shows that the MCS overall position accuracy is better than 4μm and the image processing time is less than 4 seconds. The MCS is ready for the system integration with other PFS components

Metrology camera system of prime focus spectrograph for Suburu telescope

The Prime Focus Spectrograph (PFS) is a new optical/near-infrared multi-fiber spectrograph designed for the prime focus of the 8.2m Subaru telescope. PFS will cover a 1.3 degree diameter field with 2394 fibers to complement the imaging capabilities of Hyper SuprimeCam. To retain high throughput, the final positioning accuracy between the fibers and observing targets of PFS is required to be less than 10 microns. The metrology camera system (MCS) serves as the optical encoder of the fiber motors for the configuring of fibers. MCS provides the fiber positions within a 5 microns error over the 45 cm focal plane. The information from MCS will be fed into the fiber positioner control system for the closed loop control. MCS will be located at the Cassegrain focus of Subaru telescope in order to cover the whole focal plane with one 50M pixel Canon CMOS camera. It is a 380mm Schmidt type telescope which generates a uniform spot size with a ~10 micron FWHM across the field for reasonable sampling of the point spread function. Carbon fiber tubes are used to provide a stable structure over the operating conditions without focus adjustments. The CMOS sensor can be read in 0.8s to reduce the overhead for the fiber configuration. The positions of all fibers can be obtained within 0.5s after the readout of the frame. This enables the overall fiber configuration to be less than 2 minutes. MCS will be installed inside a standard Subaru Cassgrain Box. All components that generate heat are located inside a glycol cooled cabinet to reduce the possible image motion due to heat. The optics and camera for MCS have been delivered and tested. The mechanical parts and supporting structure are ready as of spring 2016. The integration of MCS will start in the summer of 2016. In this report, the performance of the MCS components, the alignment and testing procedure as well as the status of the PFS MCS will be presented

Aberrant Sensory Gating of the Primary Somatosensory Cortex Contributes to the Motor Circuit Dysfunction in Paroxysmal Kinesigenic Dyskinesia

Paroxysmal kinesigenic dyskinesia (PKD) is conventionally regarded as a movement disorder (MD) and characterized by episodic hyperkinesia by sudden movements. However, patients of PKD often have sensory aura and respond excellently to antiepileptic agents. PRRT2 mutations, the most common genetic etiology of PKD, could cause epilepsy syndromes as well. Standing in the twilight zone between MDs and epilepsy, the pathogenesis of PKD is unclear. Gamma oscillations arise from the inhibitory interneurons which are crucial in the thalamocortical circuits. The role of synchronized gamma oscillations in sensory gating is an important mechanism of automatic cortical inhibition. The patterns of gamma oscillations have been used to characterize neurophysiological features of many neurological diseases, including epilepsy and MDs. This study was aimed to investigate the features of gamma synchronizations in PKD. In the paired-pulse electrical-stimulation task, we recorded the magnetoencephalographic data with distributed source modeling and time-frequency analysis in 19 patients of newly-diagnosed PKD without receiving pharmacotherapy and 18 healthy controls. In combination with the magnetic resonance imaging, the source of gamma oscillations was localized in the primary somatosensory cortex. Somatosensory evoked fields of PKD patients had a reduced peak frequency (p &lt; 0.001 for the first and the second response) and a prolonged peak latency (the first response p = 0.02, the second response p = 0.002), indicating the synchronization of gamma oscillation is significantly attenuated. The power ratio between two responses was much higher in the PKD group (p = 0.013), indicating the incompetence of activity suppression. Aberrant gamma synchronizations revealed the defective sensory gating of the somatosensory area contributes the pathogenesis of PKD. Our findings documented disinhibited cortical function is a pathomechanism common to PKD and epilepsy, thus rationalized the clinical overlaps of these two diseases and the therapeutic effect of antiepileptic agents for PKD. There is a greater reduction of the peak gamma frequency in PRRT2-related PKD than the non-PRRT PKD group (p = 0.028 for the first response, p = 0.004 for the second response). Loss-of-function PRRT2 mutations could lead to synaptic dysfunction. The disinhibiton change on neurophysiology reflected the impacts of PRRT2 mutations on human neurophysiology

Prime Focus Spectrograph (PFS) for the Subaru Telescope: Overview, recent progress, and future perspectives

PFS (Prime Focus Spectrograph), a next generation facility instrument on the 8.2-meter Subaru Telescope, is a very wide-field, massively multiplexed, optical and near-infrared spectrograph. Exploiting the Subaru prime focus, 2394 reconfigurable fibers will be distributed over the 1.3 deg field of view. The spectrograph has been designed with 3 arms of blue, red, and near-infrared cameras to simultaneously observe spectra from 380nm to 1260nm in one exposure at a resolution of ~1.6-2.7A. An international collaboration is developing this instrument under the initiative of Kavli IPMU. The project is now going into the construction phase aiming at undertaking system integration in 2017-2018 and subsequently carrying out engineering operations in 2018-2019. This article gives an overview of the instrument, current project status and future paths forward.Comment: 17 pages, 10 figures. Proceeding of SPIE Astronomical Telescopes and Instrumentation 201