Reduced expression of alpha-1,2-mannosidase I extends lifespan in Drosophila melanogaster and Caenorhabditis elegans

Exposure to sub-lethal levels of stress, or hormesis, was a means to induce longevity. By screening for mutations that enhance resistance to multiple stresses, we identified multiple alleles of alpha-1,2-mannosidase I (mas1) which, in addition to promoting stress resistance, also extended longevity. Longevity enhancement is also observed when mas1 expression is reduced via RNA interference in both Drosophila melanogaster and Caenorhabditis elegans. The screen also identified Edem1 (Edm1), a gene downstream of mas1, as a modulator of lifespan. As double mutants for both mas1 and Edm1 showed no additional longevity enhancement, it appeared that both mutations function within a common pathway to extend lifespan. Molecular analysis of these mutants revealed that the expression of BiP, a putative biomarker of dietary restriction (DR), is down-regulated in response to reductions in mas1 expression. These findings suggested that mutations in mas1 may extend longevity by modulating DR

INSPIRESat-1: An Ionosphere and Solar X-ray Observing MicroSat

The International Satellite Program in Research and Education’s (INSPIRE) first satellite is an Ionosphere and Solar X-ray observing microsat slated for launch in November of 2019 onboard an ISRO Polar Satellite Launch Vehicle. The microsat has a mission specific structure fitting on a PSLV ring deployer. There are two payloads aboard with two different science objectives. The Compact Ionosphere Probe (CIP) will take in-situ measurements of ion density, composition, temperature, velocity, and electron temperature. The CIP is a smaller version of the Advanced Ionosphere Probe (AIP, both developed in Taiwan) currently operating onboard the FORMOSat-5. This instrument is capable of sampling the ionosphere at 1 and 8 Hz. The second payload is the Dual Aperture X-ray Solar spectrometer (DAXSS). DAXSS is a modified Amptek X123 that will observe Solar X-rays, specifically soft X-rays. Hot plasma in the sun’s corona is best measured in the soft X-rays. Many emission lines for important elements (Fe, Si, Mg, S, etc) are in the soft X-ray range. Soft X-rays are always present in the sun but 100 times brighter during flares, these observations will also lend to understanding the temperature difference between the sun’s corona and photosphere. The solar soft x-rays are also important for the Earth’s Ionosphere, adding to the ionosphere observations made by CIP. The DAXSS instrument has heritage from a NASA calibration rocket experiment and two cubesats, MINXSS 1 and 2. The newer model Amptek X123 has much improved energy resolution for the X-ray spectrum. The primary science objectives of the INSPIRESat-1 are twofold. First, enabling the characterization of the temporal and spatial distributions of small-scale plasma irregularities like plasma bubbles and the Midnight Temperature Maximum (MTM) in season, location, and time by CIP. Second, giving a greater understanding of why the Sun’s corona is orders of magnitude hotter than the photosphere, why there is an abundance of elements change during different solar events, and how these events (observed with greater soft x-ray fidelity) effect the earth’s ionosphere. In this paper, we present science expectations for the INSPIRESat-1 and a concept for coordinated Ionospheric measurements covering several altitudes and local times using three satellite platforms carrying the same CIP instrument (INSPIRESat-1, IDEASat/INSPIRESat-2, INSPIRESat-4, FORMOSat-5). We describe the development of DAXSS and how the dual aperture prevents the need for two X123 to get the similar data. We also highlight the unique development of the INSPIRESat-1 microsat being developed by international collaboration across three different universities

Amyloid-Beta (Aβ) D7H Mutation Increases Oligomeric Aβ42 and Alters Properties of Aβ-Zinc/Copper Assemblies

Amyloid precursor protein (APP) mutations associated with familial Alzheimer's disease (AD) usually lead to increases in amyloid β-protein (Aβ) levels or aggregation. Here, we identified a novel APP mutation, located within the Aβ sequence (AβD7H), in a Taiwanese family with early onset AD and explored the pathogenicity of this mutation. Cellular and biochemical analysis reveal that this mutation increased Aβ production, Aβ42/40 ratio and prolonged Aβ42 oligomer state with higher neurotoxicity. Because the D7H mutant Aβ has an additional metal ion-coordinating residue, histidine, we speculate that this mutation may promote susceptibility of Aβ to ion. When co-incubated with Zn2+ or Cu2+, AβD7H aggregated into low molecular weight oligomers. Together, the D7H mutation could contribute to AD pathology through a “double punch” effect on elevating both Aβ production and oligomerization. Although the pathogenic nature of this mutation needs further confirmation, our findings suggest that the Aβ N-terminal region potentially modulates APP processing and Aβ aggregation, and further provides a genetic indication of the importance of Zn2+ and Cu2+ in the etiology of AD

Inter-Allelic Prion Propagation Reveals Conformational Relationships among a Multitude of [PSI] Strains

Immense diversity of prion strains is observed, but its underlying mechanism is less clear. Three [PSI] prion strains—named VH, VK, and VL—were previously isolated in the wild-type yeast genetic background. Here we report the generation and characterization of eight new [PSI] isolates, obtained by propagating the wild-type strains with Sup35 proteins containing single amino-acid alterations. The VH strain splits into two distinct strains when propagated in each of the three genetic backgrounds, harboring respectively single mutations of N21L, R28P, and Gi47 (i.e. insertion of a glycine residue at position 47) on the Sup35 N-terminal prion-forming segment. The six new strains exhibit complex inter-conversion patterns, and one of them continuously mutates into another. However, when they are introduced back into the wild-type background, all 6 strains revert to the VH strain. We obtain two more [PSI] isolates by propagating VK and VL with the Gi47 and N21L backgrounds, respectively. The two isolates do not transmit to other mutant backgrounds but revert to their parental strains in the wild-type background. Our data indicate that a large number of [PSI] strains can be built on three basic Sup35 amyloid structures. It is proposed that the three basic structures differ by chain folding topologies, and sub-strains with the same topology differ in distinct ways by local structural adjustments. This “large number of variations on a small number of basic themes” may also be operative in generating strain diversities in other prion elements. It thus suggests a possible general scheme to classify a multitude of prion strains

(1)Microwave and Ultrasound Accelerated Synthesis of 5-Cyanoindole(2)Synthesis and the Synthetic Applications of a New Chiral Hydrazine Auxiliary

本論文分為兩個部份: (一)利用微波與超音波加速5-氰基吲哚之合成 此部分報導我們使用微波與超音波大幅縮短以Russell的方法合成5-氰基吲哚之反應時間。我們使用田口法尋找最佳條件，將傳統上需要20小時之加熱的反應以微波照射3分鐘或超音波照射8分鐘，即可以得到高產率之5-溴基吲哚。此外，我們也成功地利用微波加速5-溴基吲哚之氰化反應，由18小時之傳統加熱縮短為6分鐘。我們的反應條件可大幅縮短反應時間，在工業上可大幅提高設備使用率、減低能源消耗，因此極具產業經濟價值。 (二)新掌性聯胺輔助體之合成與其在有機合成上的應用 此部分報導我們使用(+)-莰烯當起始物，經由四個步驟合成一個新掌性聯胺輔助體，N-胺基-10,10-二甲基-4-三雜環-[5,2,1,01,5]癸烷，其總產率為54%。而後將此聯胺與一系列的醛類於室溫下進行縮合反應，即可得到相對應的腙掌性模板。最後，此掌性模板於 –40ºC下與正丁基鋰進行不對稱之烷基化反應，得到產率為94% 至98% 之具光學活性的聯胺，其非鏡像超越值為58% 至89%。This thesis consists of two parts: (1)Microwave and Ultrasound Accelerated Synthesis of 5-Cyanoindole We have developed a practical and efficient synthesis of 5-cyanoindole based on Russell's process using microwave and ultrasound irradiation. Taguchi method was used to optimize the reaction conditions for achieving the highest yield of 5-bromoindole. The hydrolysis of sodium 1-acetylindoline-5-bromo-2-sulfonate was accomplished in 3 min and 8 min under microwave irradiation and ultrasonic irradiation respectively as compared to the 20 h conventional reflux method. Furthermore, the microwave-assisted cyanation of 5-bromoindole was accomplished in 6 min versus more than 18 h of thermal heating. Our methods can dramatically reduce the reaction time which, in turn, can increase the turn over rate of production equipment and decrease energy consumption and hence have economic value. (2)Synthesis and the Synthetic Applications of a New Chiral Hydrazine Auxiliary A novel synthetic approach for the preparation of the a chiral hydrazine auxiliary, N-amino-10,10-dimethyl-4-azatricyclo-[5,2,1,01,5]decane, from (+)-camphene in four steps (54% overall yield) has been established. The chiral hydrazone templates were obtained via the condensation of aldehydes and the hydrazine at room temperature. Finally, the hydrazones were stereoselectively alkylated with n-butyllithium at -40ºC to give optically active hydrazines in up to 94%~98% and 58%~89% de.中文摘要…………………………………………………………iii 英文摘要…………………………………………………………iv 壹、緒論 第一節 利用微波與超音波加速5-氰基吲哚之合成……………1 一、5-氰基吲哚及其衍生物的傳統合成方法…………………1 二、微波在有機合成上之應用…..……………………………5 三、超音波在有機合成上之應用………………………………14 四、田口法在有機合成上之應用………………………………19 第二節 新掌性聯胺輔助體之合成與應用………………………23 貳、結果與討論 第一節 利用微波與超音波加速5-氰基吲哚之合成…………44 一、由吲哚合成吲哚琳亞硫酸鈉………………………………44 二、利用微波及超音波加速5-溴基吲哚之合成………………46 三、利用微波加速5-氰基吲哚之合成…………………………53 第二節 新掌性聯胺輔助體之合成與應用……………………56 一、掌性輔助體的製備…………………………………………56 二、Hydrazone的合成……………………………………………59 三、Hydrazone的應用……………………………………………61 參、參考資料……………………………………………………66 肆、藥品與儀器…………………………………………………73 伍、實驗步驟與化合物光譜……………………………………7

Thyroid Storm Superimposed on Gestational Hypertension: A Case Report and Review of Literature

A thyroid storm is an extreme manifestation of thyrotoxicosis, and is life threatening without an early diagnosis. Pregnancy or childbirth may worsen maternal hyperthyroidism or induce the development of a thyroid storm. Gestational hypertension, a disorder defined as new-onset hypertension, develops after 20 weeks of gestation and shares symptoms with a thyroid storm. The diagnosis of a thyroid storm may be challenging in patients with gestational hypertension. To highlight the significance of early thyrotoxicosis-related gastrointestinal symptoms, we report a case of a 38-year-old woman with a twin pregnancy, who was diagnosed with gestational hypertension, and then developed a thyroid storm during the peripartum period. She complained of nausea and abdominal pain, followed by tachycardia, hypertension, and a disturbance of consciousness with desaturation. After emergency caesarean section, fever, diarrhea, and high-output heart failure, with pulmonary edema, were noted during the postoperative period in the intensive care unit. The diagnosis of a thyroid storm was confirmed using the Burch–Wartofsky point scale, which was 75 points. In this patient, the uncommon gastrointestinal symptoms, as initial manifestations of thyrotoxicosis, indicated the development of a thyroid storm. The distinguished presentation of thyrotoxicosis-induced cardiomyopathy and peripartum cardiomyopathy also helped in the differential diagnosis between a thyroid storm and gestational hypertension. Aggressive treatment for thyrotoxicosis should not be delayed because of a missed diagnosis