Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility.

To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry

Laboratory information management system for COVID-19 non-clinical efficacy trial data

Background : As the number of large-scale studies involving multiple organizations producing data has steadily increased, an integrated system for a common interoperable format is needed. In response to the coronavirus disease 2019 (COVID-19) pandemic, a number of global efforts are underway to develop vaccines and therapeutics. We are therefore observing an explosion in the proliferation of COVID-19 data, and interoperability is highly requested in multiple institutions participating simultaneously in COVID-19 pandemic research. Results : In this study, a laboratory information management system (LIMS) approach has been adopted to systemically manage various COVID-19 non-clinical trial data, including mortality, clinical signs, body weight, body temperature, organ weights, viral titer (viral replication and viral RNA), and multiorgan histopathology, from multiple institutions based on a web interface. The main aim of the implemented system is to integrate, standardize, and organize data collected from laboratories in multiple institutes for COVID-19 non-clinical efficacy testings. Six animal biosafety level 3 institutions proved the feasibility of our system. Substantial benefits were shown by maximizing collaborative high-quality non-clinical research. Conclusions : This LIMS platform can be used for future outbreaks, leading to accelerated medical product development through the systematic management of extensive data from non-clinical animal studies.This research was supported by the National research foundation of Korea(NRF) grant funded by the Korea government(MSIT) (2020M3A9I2109027 and 2021M3H9A1030260)

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

25th annual computational neuroscience meeting: CNS-2016

The same neuron may play different functional roles in the neural circuits to which it belongs. For example, neurons in the Tritonia pedal ganglia may participate in variable phases of the swim motor rhythms [1]. While such neuronal functional variability is likely to play a major role the delivery of the functionality of neural systems, it is difficult to study it in most nervous systems. We work on the pyloric rhythm network of the crustacean stomatogastric ganglion (STG) [2]. Typically network models of the STG treat neurons of the same functional type as a single model neuron (e.g. PD neurons), assuming the same conductance parameters for these neurons and implying their synchronous firing [3, 4]. However, simultaneous recording of PD neurons shows differences between the timings of spikes of these neurons. This may indicate functional variability of these neurons. Here we modelled separately the two PD neurons of the STG in a multi-neuron model of the pyloric network. Our neuron models comply with known correlations between conductance parameters of ionic currents. Our results reproduce the experimental finding of increasing spike time distance between spikes originating from the two model PD neurons during their synchronised burst phase. The PD neuron with the larger calcium conductance generates its spikes before the other PD neuron. Larger potassium conductance values in the follower neuron imply longer delays between spikes, see Fig. 17.Neuromodulators change the conductance parameters of neurons and maintain the ratios of these parameters [5]. Our results show that such changes may shift the individual contribution of two PD neurons to the PD-phase of the pyloric rhythm altering their functionality within this rhythm. Our work paves the way towards an accessible experimental and computational framework for the analysis of the mechanisms and impact of functional variability of neurons within the neural circuits to which they belong

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

SiPM-based gamma detector with a central GRIN lens for a visible/NIRF/gamma multi-modal laparoscope

Intraoperative imaging has been studied using conventional devices such as near infrared (NIR) optical probes and gamma probes. However, these devices have limited depth penetration and spatial resolution. In a previous study, we realized a multi-modal endoscopic system. However, charge-coupled device (CCD)-based gamma imaging required long acquisition times and lacked gamma energy information. A silicon photomultiplier (SiPM)-based gamma detector is implemented in a multi-modal laparoscope herein. A gradient index (GRIN) lens and CCD are used to transfer and readout visible and NIR photons. The feasibility of in-vivo sentinel lymph node (SLN) mapping was successfully performed with the proposed system

Application of CUPID for subchannel-scale thermal–hydraulic analysis of pressurized water reactor core under single-phase conditions

There have been recent efforts to establish methods for high-fidelity and multi-physics simulation with coupled thermal–hydraulic (T/H) and neutronics codes for the entire core of a light water reactor under accident conditions. Considering the computing power necessary for a pin-by-pin analysis of the entire core, subchannel-scale T/H analysis is considered appropriate to achieve acceptable accuracy in an optimal computational time. In the present study, the applicability of in-house code CUPID of the Korea Atomic Energy Research Institute was extended to the subchannel-scale T/H analysis. CUPID is a component-scale T/H analysis code, which uses three-dimensional two-fluid models with various closure models and incorporates a highly parallelized numerical solver. In this study, key models required for a subchannel-scale T/H analysis were implemented in CUPID. Afterward, the code was validated against four subchannel experiments under unheated and heated single-phase incompressible flow conditions. Thereafter, a subchannel-scale T/H analysis of the entire core for an Advanced Power Reactor 1400 reactor core was carried out. For the high-fidelity simulation, detailed geometrical features and individual rod power distributions were considered in this demonstration. In this study, CUPID shows its capability of reproducing key phenomena in a subchannel and dealing with the subchannel-scale whole core T/H analysis

Characterization and validation of multimodal annihilation-gamma/nearinfrared/visible laparoscopic system

Minimally invasive robotic surgery using fluorescence-guided images with a video laparoscope has been widely used because of its advantages of small incision, fast recovery time, and efficiency. However, the penetrationdepthlimitationoffluorescenceisadisadvantagecausedbytheabsorptionandscatteringintissues andbloodcells.Ifthislimitationcanbeovercomebyadditionalimagingmodalities,thesurgicalprocedurecanbe quiteefficient and precise. High-energy annihilation-gamma photonshavea stronger penetration capabilitythan visible and fluorescence photons. To characterize and validate a multimodal annihilation-gamma/near-infrared (NIR)/visible laparoscopic imaging system, an internal detector composed of an annihilation-gamma detector and an optical system was assembled inside a surgical stainless pipe with an outer diameter of 15.8 mm and an external detector with a dimension of 100×100 mm2 placed at the opposite side of the internal detector. Integrated images of 511-keV gamma rays, NIR fluorescence, and visible light were obtained simultaneously. The 511-keV gamma image could be clearly seen with the acquisition of 5 s, while NIR and visible images could be presented in real time. This multimodal system has the potential for improving the surgery time and the quality of patient care

Crystal surface and reflector optimization for the SiPM-based dual-ended readout TOF-DOI PET detector

Silicon photomultipliers (SiPMs) are now widely used for positron emission tomography (PET) applications because of their high gain and low noise characteristics. The PET image quality has been improved with the advancement of time-of-flight (TOF) and depth-of-interaction (DOI) measurement techniques. For brain-dedicated PET systems, both TOF and DOI information are beneficial for enhancing the reconstructed PET image quality. In a previous study, we proposed SiPM-based dualended readout PET detectors that used a mean time method to achieve coincidence timing resolution (CTR) of 349 ps and DOI resolution of 2.9 mm. However, the coincidence timing resolution (CTR) was worse than 300 ps since the crystal surface and the reflector type were not optimized. This study aimed at investigating the optimal crystal surface treatment and the reflector material to achieve a sub- 200 ps CTR and sub-3mmDOI resolution with a dual-ended readout PET detector using an LYSO crystal (2.9×2.9×20mm3). The scintillation light inside the LYSO crystal was read out by two SiPMs using the dual-ended readout method. The CTR and DOI resolution were measured with two different crystal surfaces (polished and saw-cut) and three different reflector material scenarios of ESR without grease (i.e., air coupling), ESR with optical grease and Teflon. Wedigitized the timing and energy signals by using a V775NTDCmodule (35 ps bit−1) and V965QDCmodule, respectively. The combination of the saw-cut LYSO crystal and the ESR with air coupling resulted in the best CTR (188±32 ps) and DOI resolution (2.9±0.2mm) with the dual-ended readout configuration. We concluded the dual-ended readout method in combination with the saw-cut crystal and the ESR reflector with air coupling can provide a sub-200 ps CTR and sub-3.0mmDOI resolution simultaneously