bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-dose cryo electron ptychography via non-convex Bayesian optimization
Authors: Pelz Philipp Michael , Qiu Wen Xuan , Bücker Robert , Kassier Günther , Miller R. J. Dwayne
Published: August 2017

Electron ptychography has seen a recent surge of interest for phase sensitive imaging at atomic or near-atomic resolution. However, applications are so far mainly limited to radiation-hard samples, because the required doses are too high for imaging biological samples at high resolution. We propose the use of non-convex Bayesian optimization to overcome this problem, and show via numerical simulations that the dose required for successful reconstruction can be reduced by two orders of magnitude compared to previous experiments. As an important application we suggest to use this method for imaging single biological macromolecules at cryogenic temperatures and demonstrate 2D single-particle reconstructions from simulated data with a resolution up to 5.4 Å at a dose of 20e
−
/Å2. When averaging over only 30 low-dose datasets, a 2D resolution around 3.5 Å is possible for macromolecular complexes even below 100 kDa. With its independence from the microscope transfer function, direct recovery of phase contrast, and better scaling of signal-to-noise ratio, low-dose cryo electron ptychography may become a promising alternative to Zernike phase-contrast microscopy.
Accessibility explains preferred thiol-disulfide isomerization in a protein domain
Authors: Kolšek Katra , Aponte-Santamaría Camilo , Gräter Frauke
Published: August 2017

Disulfide bonds are key stabilizing and yet potentially labile cross-links in proteins. While spontaneous disulfide rearrangement through thiol-disulfide exchange is increasingly recognized to play an important physiological role, its molecular determinants are still largely unknown. Here, we used a novel hybrid Monte Carlo and Molecular Dynamics scheme to elucidate the molecular principles of thiol-disulfide exchange in proteins, for a mutated immunoglobulin domain as a model system. Unexpectedly, using simple proximity as the criterion for thiol-disulfide exchange, our method correctly predicts the experimentally observed regiospecificity and selectivity of the cysteine-rich protein. While redox reactivity has been examined primarily on the level of transition states and activation barriers, our results argue for accessibility of the disulfide by the attacking thiol given the highly dynamic and sterically demanding protein as a major bottleneck of thiol-disulfide exchange. This scenario may be similarly at play in other proteins with or without an evolutionarily designed active site.
A novel three-dimensional culture system maintaining the physiological extracellular matrix of fibrotic model livers accelerates progression of hepatocellular carcinoma cells
Authors: Miyauchi Yuya , Yasuchika Kentaro , Fukumitsu Ken , Ishii Takamichi , Ogiso Satoshi , Minami Takahito , Kojima Hidenobu , Yamaoka Ryoya , Katayama Hokahiro , Kawai Takayuki , Yoshitoshi-Uebayashi Elena Yukie , Kita Sadahiko , Yasuda Katsutaro , Sasaki Naoya , Uemoto Shinji
Published: August 2017

Liver fibrosis is characterized by the progressive accumulation of extracellular matrix (ECM) and is a strong predictor of hepatocellular carcinoma (HCC) development and progression. However, the effect of ECM in fibrotic livers on HCC cells is poorly understood. The aims of this study were to create a new culture system that retained the natural ECM of fibrotic model livers and to establish whether natural ECM regulated the characteristics of HCC cells. Using an organ decellularization technique, we created a new culture system that preserved the tissue-specific ECM of fibrotic model livers from CCl4-treated rats. The content of ECM in fibrotic model liver scaffolds was increased and the ECM microstructure was distorted. Quantitative polymerase chain reaction and immunofluorescence assays of HCC cells cultured in fibrotic model liver scaffolds for 7 days showed an epithelial-mesenchymal transition phenotype. Moreover, the ECM of fibrotic model livers promoted proliferation and chemoresistance of HCC cells. These results showed a novel effect of natural ECM in fibrotic model livers on the malignant behaviour of HCC cells. This new culture system will be useful for both understanding the cell biology of fibrotic livers and developing novel anti-cancer drugs.
Serelaxin improves cardiac and renal function in DOCA-salt hypertensive rats
Authors: Wang Dong , Luo Yuhuan , Myakala Komuraiah , Orlicky David J. , Dobrinskikh Evgenia , Wang Xiaoxin , Levi Moshe
Published: August 2017

Serelaxin, a recombinant form of the naturally occurring peptide hormone relaxin-2, is a pleiotropic vasodilating hormone that has been studied in patients with acute heart failure. In this study, the effects of serelaxin on cardiac and renal function, fibrosis, inflammation and lipid accumulation were studied in DOCA-salt treated rats. Uninephrectomized rats were assigned to two groups: controls provided with normal drinking water and DOCA provided with DOCA pellets and sodium chloride drinking water. After 4 weeks, the DOCA-salt rats were randomly selected and implanted with osmotic minipumps delivering vehicle or serelaxin for another 4 weeks. Treatment with serelaxin prevented cardiac and renal dysfunction in DOCA-salt rats. Serelaxin prevented cardiac and renal fibrosis, as determined by Picrosirius Red staining and Second Harmonic Generation (SHG) Microscopy. Treatment of DOCA-salt rats with serelaxin decreased renal inflammation, including the expression of TGF-β, NFκB, MCP-1, IL-1, IL-6, ICAM-1, VCAM-1 and CD68 macrophages. Serelaxin also decreased lipid accumulation in kidney in part by decreasing SREBP-1c, SREBP-2, ChREBP, FATP1, HMGCoAR, and LDL receptor, and increasing Acox1 and ABCA1. In summary, serelaxin reversed DOCA-salt induced cardiac and renal dysfunction.
Therapeutic effect of human adipose-derived stem cells and their secretome in experimental diabetic pain
Authors: Brini Anna T. , Amodeo Giada , Ferreira Lorena M. , Milani Anna , Niada Stefania , Moschetti Giorgia , Franchi Silvia , Borsani Elisa , Rodella Luigi F. , Panerai Alberto E. , Sacerdote Paola
Published: August 2017

Painful neuropathy is one of the complications of diabetes mellitus that adversely affects patients’quality of life. Pharmacological treatments are not fully satisfactory, and novel approaches needed. In a preclinical mouse model of diabetes the effect of both human mesenchymal stromal cells from adipose tissue (hASC) and their conditioned medium (hASC-CM) was evaluated. Diabetes was induced by streptozotocin. After neuropathic hypersensitivity was established, mice were intravenously injected with either 1 × 106 hASC or with CM derived from 2 × 106 hASC. Both hASC and CM (secretome) reversed mechanical, thermal allodynia and thermal hyperalgesia, with a rapid and long lasting effect, maintained up to 12 weeks after treatments. In nerves, dorsal root ganglia and spinal cord of neuropathic mice we determined high IL-1β, IL-6 and TNF-α and low IL-10 levels. Both treatments restored a correct pro/antinflammatory cytokine balance and prevented skin innervation loss. In spleens of streptozotocin-mice, both hASC and hASC-CM re-established Th1/Th2 balance that was shifted to Th1 during diabetes. Blood glucose levels were unaffected although diabetic animals regained weight, and kidney morphology was recovered by treatments. Our data show that hASC and hASC-CM treatments may be promising approaches for diabetic neuropathic pain, and suggest that cell effect is likely mediated by their secretome.
Dietary glycemic index, glycemic load, and cancer risk: results from the EPIC-Italy study
Authors: Sieri S. , Agnoli C. , Pala V. , Grioni S. , Brighenti F. , Pellegrini N. , Masala G. , Palli D. , Mattiello A. , Panico S. , Ricceri F. , Fasanelli F. , Frasca G. , Tumino R. , Krogh V.
Published: August 2017

Factors linked to glucose metabolism are involved in the etiology of several cancers. High glycemic index (GI) or high glycemic load (GL) diets, which chronically raise postprandial blood glucose, may increase cancer risk by affecting insulin-like growth factor. We prospectively investigated cancer risk and dietary GI/GL in the EPIC-Italy cohort. After a median 14.9 years, 5112 incident cancers and 2460 deaths were identified among 45,148 recruited adults. High GI was associated with increased risk of colon and bladder cancer. High GL was associated with: increased risk of colon cancer; increased risk of diabetes-related cancers; and decreased risk of rectal cancer. High intake of carbohydrate from high GI foods was significantly associated with increased risk of colon and diabetes-related cancers, but decreased risk of stomach cancer; whereas high intake of carbohydrates from low GI foods was associated with reduced colon cancer risk. In a Mediterranean population with high and varied carbohydrate intake, carbohydrates that strongly raise postprandial blood glucose may increase colon and bladder cancer risk, while the quantity of carbohydrate consumed may be involved in diabetes-related cancers. Further studies are needed to confirm the opposing effects of high dietary GL on risks of colon and rectal cancers.
Graphene oxide papers with high water adsorption capacity for air dehumidification
Authors: Liu Renlong , Gong Tao , Zhang Kan , Lee Changgu
Published: August 2017

Graphene oxide (GO) has shown a high potential to adsorb and store water molecules due to the oxygen-containing functional groups on its hydrophilic surface. In this study, we characterized the water absorbing properties of graphene oxide in the form of papers. We fabricated three kinds of graphene oxide papers, two with rich oxygen functional groups and one with partial chemical reduction, to vary the oxygen/carbon ratio and found that the paper with high oxygen content has higher moisture adsorption capability. For the GO paper with reduction, the overall moisture absorbance was reduced. However, the absorbance at high humidity was significantly improved due to direct formation of multilayer water vapor in the system, which derived from the weak interaction between the adsorbent and the adsorbate. To demonstrate one application of GO papers as a desiccant, we tested grape fruits with and without GO paper. The fruits with a GO paper exhibited longer-term preservation with delayed mold gathering because of desiccation effect from the paper. Our results suggest that GO will find numerous practical applications as a desiccant and is a promising material for moisture desiccation and food preservation.
Opposite trends in the genus Monsonia (Geraniaceae): specialization in the African deserts and range expansions throughout eastern Africa
Authors: García-Aloy Sara , Sanmartín Isabel , Kadereit Gudrun , Vitales Daniel , Millanes Ana María , Roquet Cristina , Vargas Pablo , Alarcón Marisa , Aldasoro Juan José
Published: August 2017

The African Austro-temperate Flora stands out by its important species richness. A distinctive element of this flora is Monsonia (Geraniaceae), mostly found in the Namib-Karoo but also in the Natal-Drakensberg, the Somalian Zambezian and the Saharo-Arabian regions. Here, we reconstruct the evolution and biogeographic history of Monsonia based on nuclear and plastid markers, and examine the role of morphological and niche evolution in its diversification using species distribution modeling and macroevolutionary models. Our results indicate that Monsonia first diversified in the Early Miocene c.21 Ma, coinciding with the start of desertification in southwestern Africa. An important diversification occurred c. 4–6 Ma, after a general cooling trend in western South Africa and the rising of the Eastern African Mountains. The resulting two main lineages of Monsonia are constituted by: (1) Namib-Karoo succulents, and (2) herbs of the Natal-Drakensberg plus three species that further colonised steppes in north and eastern Africa. The highest diversity of Monsonia is found in the Namib-Karoo coastal belt, within a mosaic-like habitat structure. Diversification was likely driven by biome shifts and key innovations such as water-storing succulent stems and anemochorous fruits. In contrast, and unlike other arid-adapted taxa, all species of Monsonia share a C3 metabolism.
A broad range quorum sensing inhibitor working through sRNA inhibition
Authors: Jakobsen Tim H. , Warming Anders N. , Vejborg Rebecca M. , Moscoso Joana A. , Stegger Marc , Lorenzen Frederik , Rybtke Morten , Andersen Jens B. , Petersen Rico , Andersen Paal Skytt , Nielsen Thomas E. , Tolker-Nielsen Tim , Filloux Alain , Ingmer Hanne , Givskov Michael
Published: August 2017

For the last decade, chemical control of bacterial virulence has received considerable attention. Ajoene, a sulfur-rich molecule from garlic has been shown to reduce expression of key quorum sensing regulated virulence factors in the opportunistic pathogen Pseudomonas aeruginosa. Here we show that the repressing effect of ajoene on quorum sensing occurs by inhibition of small regulatory RNAs (sRNA) in P. aeruginosa as well as in Staphylococcus aureus, another important human pathogen that employs quorum sensing to control virulence gene expression. Using various reporter constructs, we found that ajoene lowered expression of the sRNAs RsmY and RsmZ in P. aeruginosa and the small dual-function regulatory RNA, RNAIII in S. aureus, that controls expression of key virulence factors. We confirmed the modulation of RNAIII by RNA sequencing and found that the expression of many QS regulated genes encoding virulence factors such as hemolysins and proteases were lowered in the presence of ajoene in S. aureus. Importantly, our findings show that sRNAs across bacterial species potentially may qualify as targets of anti-virulence therapy and that ajoene could be a lead structure in search of broad-spectrum compounds transcending the Gram negative-positive borderline.
Intestinal stem cells contribute to the maturation of the neonatal small intestine and colon independently of digestive activity
Authors: Yanai Hirotsugu , Atsumi Naho , Tanaka Toshihiro , Nakamura Naohiro , Komai Yoshihiro , Omachi Taichi , Tanaka Kiyomichi , Ishigaki Kazuhiko , Saiga Kazuho , Ohsugi Haruyuki , Tokuyama Yoko , Imahashi Yuki , Ohe Shuichi , Hisha Hiroko , Yoshida Naoko , Kumano Keiki , Kon Masanori , Ueno Hiroo
Published: August 2017

The murine intestine, like that of other mammalians, continues to develop after birth until weaning; however, whether this occurs in response to an intrinsic developmental program or food intake remains unclear. Here, we report a novel system for the allotransplantation of small intestine and colon harvested from Lgr5
EGFP-IRES-CreERT2/+; Rosa26
rbw/+ mice immediately after birth into the subrenal capsule of wild-type mice. By histological and immunohistochemical analysis, the developmental process of transplanted small intestine and colon was shown to be comparable with that of the native tissues: mature intestines equipped with all cell types were formed, indicating that these organs do not require food intake for development. The intestinal stem cells in transplanted tissues were shown to self-renew and produce progeny, resulting in the descendants of the stem cells occupying the crypt-villus unit of the small intestine or the whole crypt of the colon. Collectively, these findings indicate that neonatal intestine development follows an intrinsic program even in the absence of food stimuli.
Retrograde trafficking of β-dystroglycan from the plasma membrane to the nucleus
Authors: Gracida-Jiménez Viridiana , Mondragón-González Ricardo , Vélez-Aguilera Griselda , Vásquez-Limeta Alejandra , Laredo-Cisneros Marco S. , Gómez-López Juan de Dios , Vaca Luis , Gourlay Sarah C. , Jacobs Laura A. , Winder Steve J. , Cisneros Bulmaro
Published: August 2017

β-Dystroglycan (β-DG) is a transmembrane protein with critical roles in cell adhesion, cytoskeleton remodeling and nuclear architecture. This functional diversity is attributed to the ability of β-DG to target to, and conform specific protein assemblies at the plasma membrane (PM) and nuclear envelope (NE). Although a classical NLS and importin α/β mediated nuclear import pathway has already been described for β-DG, the intracellular trafficking route by which β-DG reaches the nucleus is unknown. In this study, we demonstrated that β-DG undergoes retrograde intracellular trafficking from the PM to the nucleus via the endosome-ER network. Furthermore, we provided evidence indicating that the translocon complex Sec61 mediates the release of β-DG from the ER membrane, making it accessible for importins and nuclear import. Finally, we show that phosphorylation of β-DG at Tyr890 is a key stimulus for β-DG nuclear translocation. Collectively our data describe the retrograde intracellular trafficking route that β-DG follows from PM to the nucleus. This dual role for a cell adhesion receptor permits the cell to functionally connect the PM with the nucleus and represents to our knowledge the first example of a cell adhesion receptor exhibiting retrograde nuclear trafficking and having dual roles in PM and NE.
Genome-Wide Linkage-Disequilibrium Mapping to the Candidate Gene Level in Melon (Cucumis melo)
Authors: Gur Amit , Tzuri Galil , Meir Ayala , Sa’ar Uzi , Portnoy Vitaly , Katzir Nurit , Schaffer Arthur A. , Li Li , Burger Joseph , Tadmor Yaakov
Published: August 2017

Cucumis melois highly diverse for fruit traits providing wide breeding and genetic research opportunities, including genome-wide association (GWA) analysis. We used a collection of 177 accessions representing the twoC. melosubspecies and 11 horticultural groups for detailed characterization of fruit traits variation and evaluation of the potential of GWA for trait mapping in melon. Through genotyping-by-sequencing, 23,931 informative SNPs were selected for genome-wide analyses. We found that linkage-disequilibrium decays at ~100 Kb in this collection and that population structure effect on association results varies between traits. We mapped several monogenic traits to narrow intervals overlapping with known causative genes, demonstrating the potential of diverse collections and GWA for mapping Mendelian traits to a candidate-gene level in melon. We further report on mapping of fruit shape quantitative trait loci (QTLs) and comparison with multiple previous QTL studies. Expansion of sample size and a more balanced representation of taxonomic groups might improve efficiency for simple traits dissection. But, as in other plant species, integrated linkage-association multi-allelic approaches are likely to produce better combination of statistical power, diversity capture and mapping resolution in melon. Our data can be utilized for selection of the most appropriate accessions for such approaches.
Upregulation of prefrontal metabotropic glutamate receptor 5 mediates neuropathic pain and negative mood symptoms after spinal nerve injury in rats
Authors: Chung Geehoon , Kim Chae Young , Yun Yeong-Chan , Yoon Sang Ho , Kim Myoung-Hwan , Kim Yu Kyeong , Kim Sang Jeong
Published: August 2017

Patients with chronic pain easily accompany the negative mood symptoms such as depression and anxiety, and these disturbances in turn affect the aversive perception of pain. However, the underlying mechanisms are largely unknown. We hypothesized that the alteration of metabotropic glutamate receptor 5 (mGluR5) in the brain region underlies such a comorbidity of aversive states. We scanned the brain of chronic neuropathic pain model rats using positron emission tomography (PET) technique with an mGluR5-selective radiotracer [11C] ABP688 and found various brain regions with higher or lower level of mGluR5 compared to control rats. Among the brain areas, a prominent upregulation of mGluR5 was shown in the prelimbic region (PrL) of the medial prefrontal cortex (mPFC) of chronic neuropathic pain animals. A pharmacological blockade of upregulated mGluR5 in the PrL ameliorated the negative symptoms including tactile hypersensitivity and depressive-like behavior, which relieved the subjects from the unpleasant state of chronic neuropathic pain condition. Conversely, lentiviral overexpression of the mGluR5 in the PrL of naïve rats successfully induced comorbid pain and negative moods. Our data provide deeper insight into the shared mechanism of pain perception and negative emotions, identifying a therapeutic target for the treatment of chronic pain and mood disorders.
Unawareness of Hepatitis B Virus Infection confers on Higher Rate of Metabolic Syndrome: A Community-based Study
Authors: Chien Cheng-Hung , Chen Li-Wei , Lin Chih-Lang , Chang Su-Wie , Shyu Yu-Chiau , Chen Kuan-Fu , Chen Shuo-Wei , Hu Ching-Chih , Yu Chia-Ying , Chien Rong-Nan
Published: August 2017

The objective of this study was to determine whether awareness of hepatitis B virus (HBV) serostatus was discordant with metabolic syndrome (MetS) among people with chronic HBV infection. We conducted a community-based study in four Taiwanese districts. A total of 3493 adult participants were recruited. Participants who were hepatitis B surface antigen (HBsAg) seropositive and had self-reported HBV infection were considered aware of hepatitis B (aHB); those who denied a history of HBV infection were considered unaware of hepatitis B (uaHB). Among the 454 participants who were HBsAg seropositive, 275 (60.6%) were aHB and 179 (39.3%) were uaHB. Hypertriglyceridemia showed significant inverse association with HBsAg seropositive, especially among those who were aHB. Insulin resistance was significantly, positively associated with HBsAg seropositive, especially among participants who were uaHB. Those who were uaHB had a higher risk of central obesity, hyperglycemia, insulin resistance, and MetS than those who were aHB (odds ratio = 2.33, 1.64, 2.15, 1.85, respectively, all p < 0.05). The association among the prevalence of MetS, its individual components and HBsAg seropositivity varies according to awareness of HBV infection. It is important to recognize an individual’s risk for MetS, especially who were unaware of HBV infection.
The Oncogenic Role of COL23A1 in Clear Cell Renal Cell Carcinoma
Authors: Xu Fujiang , Chang Kun , Ma Jian , Qu Yuanyuan , Xie Huyang , Dai Bo , Gan Hualei , Zhang Hailiang , Shi Guohai , Zhu Yao , Zhu Yiping , Shen Yijun , Ye Dingwei
Published: August 2017

Clear cell renal cell carcinoma (ccRCC) is the most common adult renal neoplasm and its incidence continues to increase. Collagen is the most abundant extracellular matrix protein in stroma, and contributes to the development and progression of ccRCC. We examined the human collagen type XXIII α1 chain (COL23A1) expression in ccRCC and the relationship between COL23A1 and patients’ survival. We found COL23A1 mRNA was elevated in tumor compared with adjacent normal tissues, which was further validated by TCGA cohort. IHC results from 151 ccRCC cases suggested that high COL23A1 expression correlated with larger tumor size (P = 0.017) and advanced T stage (P = 0.011). The overall survival (OS) was shorter for ccRCC patients with high COL23A1 expression (P = 0.002). In multivariate analysis, high COL23A1 expression was an independent prognostic factor of OS (HR: 3.024, P = 0.017). Furthermore, COL23A1 knockdown repressed proliferation of ccRCC cell lines by blocking cell cycle progression. Cell adhesion and migration capacity was also downregulated by knockdown of COL23A1. Our data indicate that COL23A1 may be a novel prognostic indicator in ccRCC and might be a specific and accessible biomarker as well as a potential new target for clinical diagnosis of ccRCC.
The cross-sectional and longitudinal effect of hyperlipidemia on knee osteoarthritis: Results from the Dongfeng-Tongji cohort in China
Authors: Zhou Min , Guo Yanjun , Wang Dongming , Shi Da , Li Weijin , Liu Yuewei , Yuan Jing , He Meian , Zhang Xiaomin , Guo Huan , Wu Tangchun , Chen Weihong
Published: August 2017

To quantify the cross-sectional and longitudinal effects of hyperlipidemia on knee osteoarthritis (KOA), we studied 13,906 middle-aged or older participants from the Dongfeng-Tongji cohort. Physical examinations were performed at baseline and follow-up. Knee pain was diagnosed by self-reported pain or stiffness. Clinical KOA was diagnosed from knee pain complains and clinical X-ray radiographs. The prevalence of knee pain and clinical KOA was 39.0% and 6.7% at baseline, respectively. Hyperlipidemia was associated with knee pain (OR 1.34, 1.23–1.45) and clinical KOA (1.34, 1.15–1.55). Compared with the participants without hyperlipidemia or use of lipid-lowering drugs, those with hyperlipidemia but no use of lipid-lowering drugs had higher risks of knee pain (1.28, 1.15–1.43) and clinical KOA (1.20, 0.97–1.48), those with hyperlipidemia and use of lipid-lowering drugs had the highest risks of knee pain (1.40, 1.26–1.56) and clinical KOA (1.45, 1.21–1.75). The risks were not elevated among participants without hyperlipidemia but using lipid-lowering drugs for prevention of other diseases. Furthermore, each 1-unit increase in triglyceride was associated with 9% and 5% increases in the risk of clinical KOA prevalence and clinical KOA onset, respectively. In conclusion, hyperlipidemia is associated with elevated risks of knee pain and clinical KOA among middle-aged or older adults.
Contribution of birth weight and adult waist circumference to cardiovascular disease risk in a longitudinal study
Authors: Tian Jingyan , Qiu Miaoyan , Li Yanyun , Zhang Xuan’e , Wang Haiyan , Sun Siming , Sharp Nora Sebeca , Tong Wenxin , Zeng Hailuan , Zheng Sheng , Song Xiaomin , Wang Weiqing , Ning Guang
Published: August 2017

To determine the association of birth weight (BW) and waist circumference (WC) on cardiovascular disease (CVD). The longitudinal cohort study consisted of 745 participants who were able to provide their birth weight information and were followed from 2002 to 2014. During the follow-up, 83 events of CVD were confirmed. After adjusting for confounding factors, subjects with birth weight <2500 g were at a significantly increased CVD risk when compared to subjects with birth weight between 2500–3999 g (OR 2·47, 95%CI, 1·07–5·71). When high waist circumference (HWC), a measurement of adult obesity, was incorporated into stratifying factors according to presence or absence of low birth weight (LBW, birth weight <2500 g), adjusted CVD risk was significantly elevated in -LBW/+ HWC group (OR 1·94, 95%CI, 1·10–3·43) and marginally significantly increased in +LBW/-HWC group (OR 2·94, 95%CI, 1·00–8·64). CVD risk was highest in subjects with LBW and HWC (+LBW/+HWC), OR 4·74 (95%CI, 1·48–15·21). Higher waist circumference in adulthood is an especially strong risk factor for cardiovascular disease among those small at birth. In this cohort, birth size and adiposity in adulthood interact to predict events of cardiovascular disease.
A novel approach for the prediction of species-specific biotransformation of xenobiotic/drug molecules by the human gut microbiota
Authors: Sharma Ashok K. , Jaiswal Shubham K. , Chaudhary Nikhil , Sharma Vineet K.
Published: August 2017

The human gut microbiota is constituted of a diverse group of microbial species harbouring an enormous metabolic potential, which can alter the metabolism of orally administered drugs leading to individual/population-specific differences in drug responses. Considering the large heterogeneous pool of human gut bacteria and their metabolic enzymes, investigation of species-specific contribution to xenobiotic/drug metabolism by experimental studies is a challenging task. Therefore, we have developed a novel computational approach to predict the metabolic enzymes and gut bacterial species, which can potentially carry out the biotransformation of a xenobiotic/drug molecule. A substrate database was constructed for metabolic enzymes from 491 available human gut bacteria. The structural properties (fingerprints) from these substrates were extracted and used for the development of random forest models, which displayed average accuracies of up to 98.61% and 93.25% on cross-validation and blind set, respectively. After the prediction of EC subclass, the specific metabolic enzyme (EC) is identified using a molecular similarity search. The performance was further evaluated on an independent set of FDA-approved drugs and other clinically important molecules. To our knowledge, this is the only available approach implemented as ‘DrugBug’ tool for the prediction of xenobiotic/drug metabolism by metabolic enzymes of human gut microbiota.
Amyloid precursor protein drives down-regulation of mitochondrial oxidative phosphorylation independent of amyloid beta
Authors: Lopez Sanchez M. Isabel G. , Waugh Hayley S. , Tsatsanis Andrew , Wong Bruce X. , Crowston Jonathan G. , Duce James A. , Trounce Ian A.
Published: August 2017

Amyloid precursor protein (APP) and its extracellular domain, soluble APP alpha (sAPPα) play important physiological and neuroprotective roles. However, rare forms of familial Alzheimer’s disease are associated with mutations in APP that increase toxic amyloidogenic cleavage of APP and produce amyloid beta (Aβ) at the expense of sAPPα and other non-amyloidogenic fragments. Although mitochondrial dysfunction has become an established hallmark of neurotoxicity, the link between Aβ and mitochondrial function is unclear. In this study we investigated the effects of increased levels of neuronal APP or Aβ on mitochondrial metabolism and gene expression, in human SH-SY5Y neuroblastoma cells. Increased non-amyloidogenic processing of APP, but not Aβ, profoundly decreased respiration and enhanced glycolysis, while mitochondrial DNA (mtDNA) transcripts were decreased, without detrimental effects to cell growth. These effects cannot be ascribed to Aβ toxicity, since higher levels of endogenous Aβ in our models do not cause oxidative phosphorylation (OXPHOS) perturbations. Similarly, chemical inhibition of β-secretase decreased mitochondrial respiration, suggesting that non-amyloidogenic processing of APP may be responsible for mitochondrial changes. Our results have two important implications, the need for caution in the interpretation of mitochondrial perturbations in models where APP is overexpressed, and a potential role of sAPPα or other non-amyloid APP fragments as acute modulators of mitochondrial metabolism.
Synthesis and Characterization of PtTe2 Multi-Crystallite Nanoparticles using Organotellurium Nanocomposites
Authors: Fernández-Lodeiro Javier , Rodríguez-Gónzalez Benito , Novio Fernando , Fernández-Lodeiro Adrián , Ruiz-Molina Daniel , Capelo José Luis , Santos Alcindo A. dos , Lodeiro Carlos
Published: August 2017

Herein, we report the synthesis of new PtTe2 multi-crystallite nanoparticles (NPs) in different sizes through an annealing process using new nanostructured Pt-Te organometallic NPs as a single source precursor. This precursor was obtained in a single reaction step using Ph2Te2 and H2PtCl6 and could be successfully size controlled in the nanoscale range. The resulting organometallic composite precursor could be thermally decomposed in 1,5 pentanediol to yield the new PtTe2 multi-crystallite NPs. The final size of the multi-crystallite spheres was successfully controlled by selecting the nanoprecursor size. The sizes of the PtTe2 crystallites formed using the large spheres were estimated to be in the range of 2.5–6.5 nm. The results provide information relevant to understanding specific mechanistic aspects related to the synthesis of organometallic nanomaterials and nanocrystals based on platinum and tellurium.
Mapping architectural and transcriptional alterations in non-lesional and lesional epidermis in vitiligo
Authors: Singh Archana , Gotherwal Vishvabandhu , Junni Päivi , Vijayan Vinaya , Tiwari Manisha , Ganju Parul , Kumar Avinash , Sharma Pankaj , Fatima Tanveer , Gupta Aayush , Holla Ananthaprasad , Kar Hemanta K. , Khanna Sangeeta , Thukral Lipi , Malik Garima , Natarajan Krishnamurthy , Gadgil Chetan J. , Lahesmaa Riitta , Natarajan Vivek T. , Rani Rajni , Gokhale Rajesh S.
Published: August 2017

In vitiligo, chronic loss of melanocytes and consequent absence of melanin from the epidermis presents a challenge for long-term tissue maintenance. The stable vitiligo patches are known to attain an irreversible depigmented state. However, the molecular and cellular processes resulting in this remodeled tissue homeostasis is unclear. To investigate the complex interplay of inductive signals and cell intrinsic factors that support the new acquired state, we compared the matched lesional and non-lesional epidermis obtained from stable non-segmental vitiligo subjects. Hierarchical clustering of genome-wide expression of transcripts surprisingly segregated lesional and non-lesional samples in two distinct clades, despite the apparent heterogeneity in the lesions of different vitiligo subjects. Pathway enrichment showed the expected downregulation of melanogenic pathway and a significant downregulation of cornification and keratinocyte differentiation processes. These perturbations could indeed be recapitulated in the lesional epidermal tissue, including blunting of rete-ridges, thickening of stratum corneum and increase in the size of corneocytes. In addition, we identify marked increase in the putrescine levels due to the elevated expression of spermine/spermidine acetyl transferase. Our study provides insights into the intrinsic self-renewing ability of damaged lesional tissue to restore epidermal functionality in vitiligo.
Impact of transient currents caused by alternating drain stress in oxide semiconductors
Authors: Lee Hyeon-Jun , Cho Sung Haeng , Abe Katsumi , Lee Myoung-Jae , Jung Minkyung
Published: August 2017

Reliability issues associated with driving metal-oxide semiconductor thin film transistors (TFTs), which may arise from various sequential drain/gate pulse voltage stresses and/or certain environmental parameters, have not received much attention due to the competing desire to characterise the shift in the transistor characteristics caused by gate charging. In this paper, we report on the reliability of these devices under AC bias stress conditions because this is one of the major sources of failure. In our analysis, we investigate the effects of the driving frequency, pulse shape, strength of the applied electric field, and channel current, and the results are compared with those from a general reliability test in which the devices were subjected to negative/positive bias, temperature, and illumination stresses, which are known to cause the most stress to oxide semiconductor TFTs. We also report on the key factors that affect the sub-gap defect states, and suggest a possible origin of the current degradation observed with an AC drive. Circuit designers should apply a similar discovery and analysis method to ensure the reliable design of integrated circuits with oxide semiconductor devices, such as the gate driver circuits used in display devices.
Hypnotic analgesia reduces brain responses to pain seen in others
Authors: Braboszcz Claire , Brandao-Farinelli Edith , Vuilleumier Patrik
Published: August 2017

Brain responses to pain experienced by oneself or seen in other people show consistent overlap in the pain processing network, particularly anterior insula, supporting the view that pain empathy partly relies on neural processes engaged by self-nociception. However, it remains unresolved whether changes in one’s own pain sensation may affect empathic responding to others’ pain. Here we show that inducing analgesia through hypnosis leads to decreased responses to both self and vicarious experience of pain. Activations in the right anterior insula and amygdala were markedly reduced when participants received painful thermal stimuli following hypnotic analgesia on their own hand, but also when they viewed pictures of others’ hand in pain. Functional connectivity analysis indicated that this hypnotic modulation of pain responses was associated with differential recruitment of right prefrontal regions implicated in selective attention and inhibitory control. Our results provide novel support to the view that self-nociception is involved during empathy for pain, and demonstrate the possibility to use hypnotic procedures to modulate higher-level emotional and social processes.
Interactions of Boron Clusters and their Derivatives with Serum Albumin
Authors: Goszczyński Tomasz M. , Fink Krzysztof , Kowalski Konrad , Leśnikowski Zbigniew J. , Boratyński Janusz
Published: August 2017

Boron clusters are polyhedral boron hydrides with unique properties, and they are becoming increasingly widely used in biology and medicine, including for boron neutron capture therapy (BNCT) of cancers and in the design of novel bioactive molecules and potential drugs. Among boron cluster types, icosahedral boranes, carboranes, and metallacarboranes are particularly interesting, and there is a need for basic studies on their interaction with biologically important molecules, such as proteins. Herein, we report studies on the interaction of selected boron clusters and their derivatives with serum albumin, the most abundant protein in mammalian blood. The interaction of boron clusters with albumin was examined by fluorescence quenching, circular dichroism, dynamic and static light scattering measurements and MALDI-TOF mass spectrometry. Our results showed that metallacarboranes have the strongest interaction with albumin among the tested clusters. The observed strength of boron cluster interactions with albumin decreases in order: metallacarboranes [M(C2B9H11)2]− > carboranes (C2B10H12) >> dodecaborate anion [B12H12]2−. Metallacarboranes first specifically interact with the binding cavity of albumin and then, with increasing compound concentrations, interact non-specifically with the protein surface. These findings can be of importance and are useful in the development of new bioactive compounds that contain boron clusters.
Selinexor (KPT-330) has antitumor activity against anaplastic thyroid carcinoma in vitro and in vivo and enhances sensitivity to doxorubicin
Authors: Garg Manoj , Kanojia Deepika , Mayakonda Anand , Ganesan Trivadi S , Sadhanandhan Bindhya , Suresh Sidhanth , S. Sneha , Nagare Rohit P. , Said Jonathan W. , Doan Ngan B. , Ding Ling-Wen , Baloglu Erkan , Shacham Sharon , Kauffman Michael , Koeffler H. Phillip
Published: August 2017

Anaplastic thyroid carcinoma (ATC) is one of the most lethal malignancies having no effective treatment. Exportin-1 (XPO1) is the key mediator of nuclear export of many tumor suppressor proteins and is overexpressed in human cancers. In this study, we examined the therapeutic potential of selinexor (XPO1 inhibitor) against human ATC cells both in vitro and in vivo. Here, we showed that XPO1 is robustly expressed in primary ATC samples and human ATC cell lines. Silencing of XPO1 by either shRNA or selinexor significantly reduced cellular growth and induced cell cycle arrest, apoptosis of ATC cells by altering the protein expression of cancer-related genes. Moreover, selinexor significantly inhibited tumor growth of ATC xenografts. Microarray analysis showed enrichment of DNA replication, cell cycle, cell cycle checkpoint and TNF pathways in selinexor treated ATC cells. Importantly, selinexor decreased AXL and GAS6 levels in CAL62 and HTH83 cells and suppressed the phosphorylation of downstream targets of AXL signaling such as AKT and P70S6K. Finally, a combination of selinexor with doxorubicin demonstrated a synergistic decrease in the cellular proliferation of several ATC cells. These results provide a rationale for investigating the efficacy of combining selinexor and doxorubicin therapy to improve the outcome of ATC patients.
Giant THz surface plasmon polariton induced by high-index dielectric metasurface
Authors: Lin Shuai , Bhattarai Khagendra , Zhou Jiangfeng , Talbayev Diyar
Published: August 2017

We use computational approaches to explore the role of a high-refractive-index dielectric TiO2 grating with deep subwavelength thickness on InSb as a tunable coupler for THz surface plasmons. We find a series of resonances as the grating couples a normally-incident THz wave to standing surface plasmon waves on both thin and thick InSb layers. In a marked contrast with previously-explored metallic gratings, we observe the emergence of a much stronger additional resonance. The mechanism of this giant plasmonic resonance is well interpreted by the dispersion of surface plasmon excited in the air\TiO2\InSb trilayer system. We demonstrate that both the frequency and the intensity of the giant resonance can be tuned by varying dielectric grating parameters, providing more flexible tunability than metallic gratings. The phase and amplitude of the normally-incident THz wave are spatially modulated by the dielectric grating to optimize the surface plasmon excitation. The giant surface plasmon resonance gives rise to strong enhancement of the electric field above the grating structure, which can be useful in sensing and spectroscopy applications.
A novel function of cIAP1 as a mediator of CHIP-driven eIF4E regulation
Authors: Seo Tae Woong , Lee Ji Sun , Choi Ye Na , Jeong Dar Heum , Lee Sun Kyung , Yoo Soon Ji
Published: August 2017

eIF4E is an initiator protein in cap-dependent translation. Its overexpression is linked to tumorigenesis in various human cancers, suggesting that the levels of eIF4E must be under tight control in normal cells. Although several eIF4E regulatory mechanisms have been demonstrated, the intracellular mechanisms controlling eIF4E protein levels remain poorly understood. Here, we report that eIF4E is efficiently regulated by dual mechanisms, both involving human inhibitor of apoptosis family protein cIAP1. cIAP1 itself ubiquitinates eIF4E as an E3 ligase, and interestingly, cIAP1 also functions as a mediator to present eIF4E to another E3 ligase, CHIP. This collaborative activity of cIAP1 and CHIP directs eIF4E toward degradation, controlling its levels and suppressing tumorigenesis. Our results provide the first evidence for a mediator function of cIAP1 and collaborative activity of cIAP1 and CHIP, suggesting that maintaining balanced levels of these E3 ligases might be beneficial for normal cell growth.
A novel chalcone derivative S17 induces apoptosis through ROS dependent DR5 up-regulation in gastric cancer cells
Authors: Zhang Saiyang , Li Tingyu , Zhang Li , Wang Xiangyu , Dong Hangqi , Li Lili , Fu Dongjun , Li Yongchun , Zi Xiaolin , Liu Hong-Min , Zhang Yanbing , Xu Hongde , Jin Cheng-Yun
Published: August 2017

A new series of etherification chalcone derivatives were designed and synthesized through Willimison etherification and Claisen-Schmidt condensation. Among them, compound 2-c which was given chemical name of S17, has been successfully screened out as the most potent one on gastric cancer cell line(MGC803) through the investigation for their effects against the growth of five cancer cell lines (EC109, HepG2, MCF7, MGC803, SKNSH). S17 exhibited strong anti-proliferative activity on other two gastric cancer cells (HGC27 and SGC7901), but less cytotoxicity to non-malignant gastric epithelial cells GES1. S17 potently killed gastric cancer cells with causing modulation of Bcl-2 family proteins and activation of caspase 9/3 cascade. S17 also up-regulated DR5 expression and DR5 knockdown partially reversed S17-induced apoptosis, caspase activation and MMP decrease. S17 robustly induced generation of ROS with Keap/Nrf2 pathway activated and the application of ROS scavenger N-acetyl cysteine (NAC) completely blocked these effects by S17 in MGC803 cells. Intraperitoneal administration of S17 significantly inhibited the growth of MGC803 cells in vivo in a xenograft mouse model without observed toxicity. These results indicated that S17 is a leadbrominated chalcone derivate and deserves further investigation for prevention and treatment of gastric cancer.
Inhibition of GDF8 (Myostatin) accelerates bone regeneration in diabetes mellitus type 2
Authors: Wallner Christoph , Jaurich Henriette , Wagner Johannes Maximilian , Becerikli Mustafa , Harati Kamran , Dadras Mehran , Lehnhardt Marcus , Behr Björn
Published: August 2017

Metabolic diseases like diabetes mellitus cause bone healing deficiencies. We found significant impairment of bone regeneration, osteogenic differentiation and proliferation in diabetic bone. Moreover recent studies suggest a highly underestimated importance of GDF8 (Myostatin) in bone metabolism. Our goal was to analyze the role of GDF8 as a regulator of osteogenic differentiation, proliferation and bone regeneration. We used a murine tibial defect model in diabetic (Leprdb−/−) mice. Myostatin-Inhibitor Follistatin was administered in tibial bony defects of diabetic mice. By means of histology, immunohistochemistry and QRT-PC osteogenesis, differentiation and proliferation were analyzed. Application of Myostatin-inhibitor showed a significant improvement in diabetic bone regeneration compared to the control group (6.5 fold, p < 0.001). Immunohistochemistry revealed a significantly higher proliferation (7.7 fold, p = 0.009), osteogenic differentiation (Runx-2: 3.7 fold, p = 0.011, ALP: 9.3 fold, p < 0.001) and calcification (4.9 fold, p = 0.024) in Follistatin treated diabetic animals. Therapeutical application of Follistatin, known for the importance in muscle diseases, plays an important role in bone metabolism. Diabetic bone revealed an overexpression of the catabolic protein Myostatin. Antagonization of Myostatin in diabetic animals leads to a restoration of the impaired bone regeneration and represents a promising therapeutic option.
The extraordinary variation of the organellar genomes of the Aneura pinguis revealed advanced cryptic speciation of the early land plants
Authors: Myszczyński Kamil , Bączkiewicz Alina , Buczkowska Katarzyna , Ślipiko Monika , Szczecińska Monika , Sawicki Jakub
Published: August 2017

Aneura pinguisis known as a species complex with several morphologically indiscernible species, which are often reproductively isolated from each other and show distinguishable genetic differences. Genetic dissimilarity of cryptic species may be detected by genomes comparison. This study presents the first complete sequences of chloroplast and mitochondrial genomes of six cryptic species ofA. pinguiscomplex:A. pinguisA, B, C, E, F, J. These genomes have been compared to each other in order to reconstruct phylogenetic relationships and to gain better understanding of the evolutionary process of cryptic speciation in this complex. The chloroplast genome with the nucleotide diversity 0.05111 and 1537 indels is by far more variable than mitogenome with π value 0.00233 and number of indels 1526. Tests of selection evidenced that on about 36% of chloroplast genes and on 10% of mitochondrial genes ofA. pinguisacts positive selection. It suggests an advanced speciation of species. The phylogenetic analyses based on genomes show thatA. pinguisis differentiated and forms three distinct clades. Moreover, on the cpDNA trees,Aneura mirabilisis nested among the cryptic species ofA. pinguis. This indicates that theA. pinguiscryptic species do not derive directly from one common ancestor.