Genetic Drivers of Heterogeneity in Type 2 Diabetes Pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P \u3c 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes1,2 and molecular mechanisms that are often specific to cell type3,4. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P &lt; 5 × 10-8) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores5 in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.</p

Assessment of Moisture Distribution in Individual Rice Kernels Using Magnetic Resonance Imaging

本研究應用磁振影像探討單粒稻穀內部靜態水份分佈，以及在均化與浸泡過程中，內部水份經擴散與對流作用所產生之動態變化。實驗過程分別使用3.0T MRI系統之SPI脈衝序列，以及9.4T MRI系統之3D Spin echo脈衝序列進行磁振造影。首先藉由磁振造影機之參數設定試驗以取得較佳的影像，再由影像的分析探討稻穀內部水份之分佈與動態遷移。粒稻穀在平衡含水率下，磁振影像訊號強度並非均質且分成幾個部份，其中胚的訊號強度最高，糊粉層的強度次之，胚乳相較前兩者其訊號強度較低。在均化試驗中，稻穀以55℃熱風乾燥30分鐘之後進行均化，由於內外層之水份梯度，造成水份的擴散作用，過程中內層之擴散速度高於外層，呈現雙項指數函數的關係，兩項指數代表之意義，一者為內部水分子的擴散現象，另一者為通風環境下，受對流作用迫使水分子加速往外遷移。其結果顯示良好的通風將有助於單粒稻穀內部之均化，均化時間大約在7小時，其內外層水份可達平衡，若無通風的情況下均化時間將高達15小時以上，此遷移多發生在胚乳上，而胚很快即達到平衡，糊粉層的水份差異性並不大。稻穀直接浸泡的實驗中，水份經由稻殼滲透與珠孔的傳導而進入穀體內，而於胚及胚乳間擴散開來。期間米心之水份吸收可分為4個時期，由最初之遲滯時期，而到達較快速的水份增升期，而後為另一緩升時期，最後到達飽和之含水率。稻穀直接浸泡、珠孔導水、封住珠孔稻穀浸泡與封住稻殼僅以珠孔導水等四種不同的浸泡模式中，米心達飽和含水率67%需時分別約為7、17、22與32小時，在浸泡過程的兩個傳輸通路中以珠孔的傳水效率較快，而水份透過稻殼的傳輸較慢。The objectives of this research are to investigate the static moisture distribution within an individual rice kernel, and the dynamic moisture migration during tempering and soaking using MRI techniques. Experiments were performed separately using SPI pulse sequences in a 3T MRI system and 3D spin echo sequences in a 9.4T MRI system for image acquisition under various experimental conditions. The optimum MRI acquisition parameters were initially studied and determined for later experimentation for the assessment of static and dynamic moisture migration behaviors within individual rice kernels.or rice kernel at equilibrium moisture content, the MR signals spatially non-homogeneous. A rice kernel has the strongest signal intensity at its embryo part. The aleurone layer has relatively weaker signal intensity while the endosperm part exhibits the least signal intensity. The signal intensity of the endosperm increases as the moisture content increases. In the tempering experiments, the rice kernels were air-dried for 30 minutes at 55℃ before image acquisition. The dynamic moisture migration was observed due to the existence of moisture gradient and the diffusion process. The transient change of the signal intensities in the endosperm was well fitted with a double exponential function suggesting that both convection and diffusion contributed to the reduction of the moisture gradient within the rice kernel during tempering. This hypothesis was further supported by the experimental data of the insulated rice kernel whose convective mass transfer was excluded. The tempering time was about 7 hours when the moisture gradient of the endosperm became minimal. The tempering time was about 15 hours for the insulated rice kernel without convective mass transfer.RI experiments were also designed to assess the moisture migration within rice kernels under various soaking conditions. Moisture can either transport across the rice husk or via the micropyle. The dynamic change of moisture content at the central part of the endosperm was observed to have four phases: initial lag phase, rapid increase phase, slow increase phase, and the saturation phase. For the four test conditions: direct soaking, guided micropyle transport, sealed micropyle, and insulated husk, the time required to reach 67% moisture saturation at the central endosperm was 7, 17, 22 and 32 hours, respectively. The rate of moisture transport via micropyle appeared to be faster compare with the moisture transport across the rice husk.誌 謝 III 要 IVBSTRACT V目錄 VIII目錄 XI一章 緒論 1.1 前言 1.2 研究目的 2.3 論文內容 3二章 文獻探討 4.1 稻穀的特性 4.1.1 稻穀的生理 4.1.2 稻穀乾燥作業 5.2 核磁共振(NMR) 8.2.1 核磁共振基本理論 8.2.2 核磁共振在農業上的應用 10.3 磁振影像(MRI) 10.3.1 磁振影像之基礎 10.3.2 磁振影像之水分子訊號 11.4 磁共振技術在穀物上的應用 12.5 單粒稻穀擴散模式之建立 13三章 研究設備與方法 15.1 研究設備 15.1.1 3.0T磁振造影設備 15.1.2 9.4T磁振造影設備 17.1.3 乾燥與稱重設備 18.1.4 影像分析軟體 18.2 研究方法 19.2.1 研究材料 19.2.2 稻穀之含水率量測 20.2.3 以核磁共振儀進行單粒稻穀水份分佈之造影 21.2.4 單粒稻穀之含水率與磁振影像強度關係試驗 24.2.5 單粒稻穀均化之磁振影像試驗 24.2.6 單粒稻穀浸潤之磁振影像試驗 26四章 結果與討論 29.1 以3.0T磁振造影之參數設定 29.1.1 視野(FOV)之影響 29.1.2 影像矩陣(Matrix)之影響 31.1.3 回音時間(TE)與重複時間(TR)之影響 32.1.4 掃描次數(NEX)之影響 33.1.5 脈衝角度與脈衝長度對訊號之影響 35.2 以9.4T磁振造影之參數設定 38.2.1 Muti-Echo Testing 38.2.2 3D Spin Echo Testing 41.3 單粒稻穀之磁振影像 44.3.1 新收穫與乾燥後稻穀之水份分佈 46.3.2 單粒稻穀之高解析度磁振影像 51.3.3 單粒稻穀之3.0T MRI各切面磁振造影 54.3.4 單粒稻穀之9.4T MRI各切面磁振造影 56.3.5 磁振影像訊號與單粒稻穀之含水率 61.4 單粒稻穀均化之磁振影像 63.4.1 自然對流之均化過程水份分佈變化 64.4.2 無對流之均化過程水份分佈變化 73.5 單粒稻穀浸泡之磁振影像 78.5.1 稻穀直接浸泡之水份分佈變化 78.5.2 珠孔封閉帶殼浸泡之水份分佈變化 92.5.3 珠孔導水之水份分佈變化 100.5.4 珠孔單側導水之水份分佈變化 108.5.5 剝殼浸泡之水份分佈變化 117.5.7 不同浸泡模式之比較 123五章 結論與建議 125.1結論 125.2建議 126考文獻 12

Effect of Gas Counter Pressure on the Surface Roughness, Morphology, and Tensile Strength between Microcellular and Conventional Injection-Molded PP Parts

Microcellular injection-molded parts have surface defect problems. Gas counter pressure (GCP) is one of the methods to reduce surface defects. This study investigated the effect of GCP on the surface roughness, morphology, and tensile strength of foamed and conventional injection-molded polypropylene (PP) products. GCP is generated by filling up the mold cavity with nitrogen during the injection-molding (IM) process. It can delay foaming and affect flow characteristics of microcellular and conventional injection-molding, which cause changes in the tensile strength, flow length, cell morphology, and surface quality of molded parts. The mechanism was investigated through a series of experiments including tuning of GCP and pressure holding duration. Surface roughness of the molded parts decreased with the increase in GCP and pressure holding duration. Compared to microcellular IM, GCP-assisted foaming exhibited much better surface quality and controllable skin layer thickness

Processing Effects on the Through-Plane Electrical Conductivities and Tensile Strengths of Microcellular-Injection-Molded Polypropylene Composites with Carbon Fibers

Polymers reinforced with conducting fibers to achieve electrical conductivity have attracted remarkable attention in several engineering applications, and injection molding provides a cost-effective way for mass production. However, the electrical performance usually varies with the molding conditions. Moreover, high added content of conducting fibers usually results in molding difficulties. In this study, we propose using microcellular (MuCell) injection molding for polypropylene (PP)/carbon fiber (CF, 20, and 30 wt%) composites and hope that the MuCell injection molding process can improve both electrical and mechanical performance as compared with conventional injection molded (CIM) parts under the same CF content. Both molding techniques were also employed with and without gas counter pressure (GCP), and the overall fiber orientation, through-plane electrical conductivity (TPEC), and tensile strength (TS) of the composites were characterized. Based on the various processing technologies, the results can be described in four aspects: (1) Compared with CIM, microcellular foaming significantly influenced the fiber orientation, and the TPECs of the samples with 20 and 30 wt% CF were 18&ndash;78 and 5&ndash;8 times higher than those of the corresponding samples molded by CIM, respectively; (2) when GCP was employed in the CIM process, the TPEC of the samples with 20 and 30 wt% CF increased by 3 and 2 times, respectively. Similar results were obtained in the case of microcellular injection molding&mdash;the TPEC of the 20 and 30 wt% composites increased by 7&ndash;74 and 18&ndash;32 times, respectively; (3) although microcellular injection molding alone (i.e., without GCP) showed the greatest influence on the randomness of the fiber orientation and the TPEC, the TS of the samples was the lowest due to the uncontrollable foaming cell size and cell size uniformity; (4) in contrast, when GCP was employed in the microcellular foaming process, high TS was obtained, and the TPEC was significantly enhanced. The high foaming quality owing to the GCP implementation improved the randomness of fiber orientation, as well as the electrical and mechanical properties of the composites. Generally speaking, microcellular injection combined with gas counter pressure does provide a promising way to achieve high electrical and mechanical performance for carbon-fiber-added polypropylene composites