FAM129B, an antioxidative protein, reduces chemosensitivity by competing with Nrf2 for Keap1 binding.

BackgroundThe transcription factor Nrf2 is a master regulator of antioxidant response. While Nrf2 activation may counter increasing oxidative stress in aging, its activation in cancer can promote cancer progression and metastasis, and confer resistance to chemotherapy and radiotherapy. Thus, Nrf2 has been considered as a key pharmacological target. Unfortunately, there are no specific Nrf2 inhibitors for therapeutic application. Moreover, high Nrf2 activity in many tumors without Keap1 or Nrf2 mutations suggests that alternative mechanisms of Nrf2 regulation exist.MethodsInteraction of FAM129B with Keap1 is demonstrated by immunofluorescence, colocalization, co-immunoprecipitation and mammalian two-hybrid assay. Antioxidative function of FAM129B is analyzed by measuring ROS levels with DCF/flow cytometry, Nrf2 activation using luciferase reporter assay and determination of downstream gene expression by qPCR and wester blotting. Impact of FAM129B on in vivo chemosensitivity is examined in mice bearing breast and colon cancer xenografts. The clinical relevance of FAM129B is assessed by qPCR in breast cancer samples and data mining of publicly available databases.FindingsWe have demonstrated that FAM129B in cancer promotes Nrf2 activity by reducing its ubiquitination through competition with Nrf2 for Keap1 binding via its DLG and ETGE motifs. In addition, FAM129B reduces chemosensitivity by augmenting Nrf2 antioxidative signaling and confers poor prognosis in breast and lung cancer.InterpretationThese findings demonstrate the important role of FAM129B in Nrf2 activation and antioxidative response, and identify FMA129B as a potential therapeutic target. FUND: The Chang Gung Medical Foundation (Taiwan) and the Ministry of Science and Technology (Taiwan)

Ferulic Acid, an Angelica sinensis

Membranous nephropathy (MN) is a leading cause of adult nephrotic syndrome but lacks adequate treatment. Different extracts of Angelica sinensis (AS) and one of its active compounds, ferulic acid (FA), were used to evaluate the therapeutic effects in a MN mouse model. The MN model was grouped into three subgroups: no treatment (N-T), treatment at induction of MN (Pre-T), and treatment after full-blown MN (Post-T). The results showed that the methanol (ME) layer of AS extract exhibited a therapeutic effect on MN-induced proteinuria. The ME layer-enriched compound, FA, improved the hypoalbuminemia, hyperlipidemia, and proteinuria in both Pre-T and Post-T groups. Ferulic acid also reduced the formation of oxidative protein products and increased the synthesis of antioxidant enzymes in groups Pre-T and Post-T. Regarding angiogenesis factors, the antiangiogenic factors in renal glomeruli were increased in group N-T, but, after FA treatment, only one of the antiangiogenic factors, thrombospondin-1, showed a significant decrease. Furthermore, the expression of Th2 predominant showed significant decrease in both Pre-T and Post-T groups when compared to that of N-T group. In summary, FA retarded the progression of MN, and the mechanisms involved the regulation of oxidative stresses, angiogenic and antiangiogenic factors, and attenuation of Th2 response

Numerical study of the thermoelectric power factor in ultra-thin Si nanowires

Low dimensional structures have demonstrated improved thermoelectric (TE) performance because of a drastic reduction in their thermal conductivity, {\kappa}l. This has been observed for a variety of materials, even for traditionally poor thermoelectrics such as silicon. Other than the reduction in {\kappa}l, further improvements in the TE figure of merit ZT could potentially originate from the thermoelectric power factor. In this work, we couple the ballistic (Landauer) and diffusive linearized Boltzmann electron transport theory to the atomistic sp3d5s*-spin-orbit-coupled tight-binding (TB) electronic structure model. We calculate the room temperature electrical conductivity, Seebeck coefficient, and power factor of narrow 1D Si nanowires (NWs). We describe the numerical formulation of coupling TB to those transport formalisms, the approximations involved, and explain the differences in the conclusions obtained from each model. We investigate the effects of cross section size, transport orientation and confinement orientation, and the influence of the different scattering mechanisms. We show that such methodology can provide robust results for structures including thousands of atoms in the simulation domain and extending to length scales beyond 10nm, and point towards insightful design directions using the length scale and geometry as a design degree of freedom. We find that the effect of low dimensionality on the thermoelectric power factor of Si NWs can be observed at diameters below ~7nm, and that quantum confinement and different transport orientations offer the possibility for power factor optimization.Comment: 42 pages, 14 figures; Journal of Computational Electronics, 201

Вихретоковый анизотропный термоэлектрический первичный преобразователь лучистого потока

Представлена оригинальная конструкция первичного преобразователя лучистого потока, который может служить основой для создания приемника неселективного излучения с повышенной чувствительностью

The 5p15.33 Locus Is Associated with Risk of Lung Adenocarcinoma in Never-Smoking Females in Asia

Genome-wide association studies of lung cancer reported in populations of European background have identified three regions on chromosomes 5p15.33, 6p21.33, and 15q25 that have achieved genome-wide significance with p-values of 10−7 or lower. These studies have been performed primarily in cigarette smokers, raising the possibility that the observed associations could be related to tobacco use, lung carcinogenesis, or both. Since most women in Asia do not smoke, we conducted a genome-wide association study of lung adenocarcinoma in never-smoking females (584 cases, 585 controls) among Han Chinese in Taiwan and found that the most significant association was for rs2736100 on chromosome 5p15.33 (p = 1.30×10−11). This finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls (p = 5.38×10−11). A pooled analysis achieved genome-wide significance for rs2736100. This SNP marker localizes to the CLPTM1L-TERT locus on chromosome 5p15.33 (p = 2.60×10−20, allelic risk = 1.54, 95% Confidence Interval (CI) 1.41–1.68). Risks for heterozygote and homozygote carriers of the minor allele were 1.62 (95% CI; 1.40–1.87), and 2.35 (95% CI: 1.95–2.83), respectively. In summary, our results show that genetic variation in the CLPTM1L-TERT locus of chromosome 5p15.33 is directly associated with the risk of lung cancer, most notably adenocarcinoma

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population.

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications

Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P interaction  = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications

Transcription termination in vitro by chloroplast RNA polymerase

Spinach chloroplast RNA polymerase from crude lysates was able to recognize bacterial histidine and threonineterminators. To determine whether chloroplast RNA polymerase would terminate other baterial terminators invitro,several terminators isolated from the attenuators of E.coli amino acid operons, such as leu, trp, ilvGEDA, phe and ilvB, were transcribed by spinach chloroplast RNA polymerase and T7 RNA polymerase. The termination efficiency of each terminater was quantitated with laser densitometry. Transcription results reveal that the chloroplast and T7 RNA polymerases did terminate transcription at different terminators with varying efficiencies. The thr terminator wass till observed as the most efficient terminator. Previous studies with thr terminator mutants indicatedthat the transcription termination efficiency of thrterminator by spinach chloroplast RNA polymerase was modulated by a not-yet- transcribed 5 bases ( CGACT ) DNA sequences. These 5 bases are located immediately from the termination release site. To further characterize the effect of these 5bases on termination, a series of systematic mutants for these 5 bases were created by PCR with a mixed primer. These thr variants were then transcribed in vitro by chloroplast or T7 RNA polymerase. Transcription by chloroplast RNA polymerase indicated that the second base of these 5 bases is important for determining the terminationefficiency.However, the transcription termination by T7 RNA polymerase did not reveal any difference among these mutants.These results suggested that the termination process of chloroplast RNA polymerase is complex and differs from T7 RNA polymerase.由於構造及功能上的相近，菠菜葉綠體 RNA 聚合脢的轉錄終止特性與原 核生物 rho-independent 終止子有許多相似之處。為了對葉綠體的轉錄 終止機制有更多的了解，本實驗以生體外轉錄系統， 分二方面探討葉綠 體 RNA 聚合脢的轉錄終止特性。一、菠菜葉綠體 RNA 聚合脢對細菌致弱 子的辨認：本實驗根據已發表的幾種大腸桿菌致弱子核酸序列， 以聚合 脢連鎖反應的方法由大腸桿菌基因組中， 增殖出各種不同的致弱子核酸 片段。這些致弱子進一步構築至含有葉綠體起動子( PLs )的質體上，以 生體外轉錄的方法分析各種致弱子轉錄終止的效率。 結果顯示各種致弱 子有強弱不同的轉錄終止效率，但仍以酥胺酸致弱子的轉錄終止效率最高 。二、大腸桿菌酥胺酸致弱子下游核酸序列對轉錄終止效率之影響 ：利 用葉綠體 RNA 聚合脢酥胺酸終止子刪除突變株進行生體外轉錄終止分析 的結果，發現酥胺酸終止子３′端 poly T 下游５個鹽基( CGACT )核酸 序列的組成對轉錄終止效率有重大的影響。 於是本實驗再度應用聚合脢 連鎖反應的方法，將酥胺酸 poly T 後 ５個鹽基核酸序列以混合引子的 方法，造成這 ５個鹽基逢機的重新排列組合，並配合生體外轉錄的分析 ， 探討終止子下游核酸序列與轉錄終止效率間的關係。這部分結果顯示 在葉綠體 RNA 聚合脢轉錄下，這５個鹽基序列的重新組合的確造成轉錄 終止效率的不同，但在噬菌體 T7 RNA 聚合脢進行轉錄時， 這段終止子 下游核酸序列的變化，卻對轉錄終止效率沒有太大的影響。 綜合轉錄的 結果，發現在葉綠體 RNA 聚合脢生體外轉錄下， 具有" T8CGANN "下游 核酸序列的酥胺酸終止子突變株，有較高的轉錄終止效率。 進一步的分 析顯示" T8CGANN "序列中的"G"鹽基，可能帶有終止轉錄反應的重要訊 息。 綜合這些結果並參考相關的文獻，目前認為這段終止子下游的核酸 序列，可能與 RNA 聚合脢在轉錄終止發生時的轉位 (translocation)反 應有關。但確實的影響機制仍待多方面的分析與試驗