bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tsc1 deficiency impairs mammary development in mice by suppression of AKT, nuclear ERα and cell-cycle-driving proteins
Authors: Qin Zhenqi , Zheng Hang , Zhou Ling , Ou Yanhua , Huang Bin , Yan Bo , Qin Zhenshu , Yang Cuilan , Su Yongchun , Bai Xiaochun , Guo Jiasong , Lin Jun 
Published: January 2016

AbstractLoss of Tsc1/Tsc2 results in excess cell growth that eventually forms hamartoma in multiple organs. Our study using a mouse model with Tsc1 conditionally knockout in mammary epithelium showed that Tsc1 deficiency impaired mammary development. Phosphorylated S6 was up-regulated in Tsc1−/− mammary epithelium, which could be reversed by rapamycin, suggesting that mTORC1 was hyperactivated in Tsc1−/− mammary epithelium. The mTORC1 inhibitor rapamycin restored the development of Tsc1−/− mammary glands whereas suppressed the development of Tsc1wt/wt mammary glands, indicating that a modest activation of mTORC1 is critical for mammary development. Phosphorylated PDK1 and AKT, nuclear ERα, nuclear IRS-1, SGK3 and cell cycle regulators such as Cyclin D1, Cyclin E, CDK2, CDK4 and their target pRB were all apparently down-regulated in Tsc1−/− mammary glands, which could be reversed by rapamycin, suggesting that suppression of AKT by hyperactivation of mTORC1, inhibition on nuclear ERα signaling and down-regulation of cell-cycle-driving proteins play important roles in the retarded mammary development induced by Tsc1 deletion. This study demonstrated for the first time the in vivo role of Tsc1 in pubertal mammary development of mice and revealed that loss of Tsc1 does not necessarily lead to tissue hyperplasia.
Heme oxygenase-1 is dispensable for the anti-inflammatory activity of intravenous immunoglobulin
Authors: Galeotti Caroline , Hegde Pushpa , Das Mrinmoy , Stephen-Victor Emmanuel , Canale Fernando , Muñoz Marcos , Sharma Varun K. , Dimitrov Jordan D. , Kaveri Srini V. , Bayry Jagadeesh 
Published: January 2016

AbstractIntravenous immunoglobulin G (IVIG) is used in the therapy of various autoimmune and inflammatory conditions. The mechanisms by which IVIG exerts anti-inflammatory effects are not completely understood. IVIG interacts with numerous components of the immune system including dendritic cells, macrophages, T and B cells and modulate their functions. Recent studies have reported that heme oxygenase-1 (HO-1) pathway plays an important role in the regulation of inflammatory response in several pathologies. Several therapeutic agents exert anti-inflammatory effects via induction of HO-1. Therefore, we aimed at exploring if anti-inflammatory effects of IVIG are mediated via HO-1 pathway. Confirming the previous reports, we report that IVIG exerts anti-inflammatory effects on innate cells as shown by the inhibitory effects on IL-6 and nitric oxide production and confers protection in experimental autoimmune encephalomyelitis (EAE) model. However, these effects were not associated with an induction of HO-1 either in innate cells such as monocytes, dendritic cells and macrophages or in the kidneys and liver of IVIG-treated EAE mice. Also, inhibition of endogenous HO-1 did not modify anti-inflammatory effects of IVIG. These results thus indicate that IVIG exerts anti-inflammatory effects independent of HO-1 pathway.
The frontline antibiotic vancomycin induces a zinc starvation response in bacteria by binding to Zn(II)
Authors: Zarkan Ashraf , Macklyne Heather-Rose , Truman Andrew W. , Hesketh Andrew R. , Hong Hee-Jeon 
Published: January 2016

AbstractVancomycin is a front-line antibiotic used for the treatment of nosocomial infections, particularly those caused by methicillin-resistantStaphylococcus aureus. Despite its clinical importance the global effects of vancomycin exposure on bacterial physiology are poorly understood. In a previous transcriptomic analysis we identified a number of Zur regulon genes which were highly but transiently up-regulated by vancomycin inStreptomyces coelicolor. Here, we show that vancomycin also induces similar zinc homeostasis systems in a range of other bacteria and demonstrate that vancomycin binds to Zn(II)in vitro. This implies that vancomycin treatment sequesters zinc from bacterial cells thereby triggering a Zur-dependent zinc starvation response. The Kd value of the binding between vancomycin and Zn(II) was calculated using a novel fluorometric assay and NMR was used to identify the binding site. These findings highlight a new biologically relevant aspect of the chemical property of vancomycin as a zinc chelator.
Two Genetic Variations in the IRF8 region are associated with Behçet’s disease in Han Chinese
Authors: Jiang Yanni , Wang Hong , Yu Hongsong , Li Lin , Xu Dengfeng , Hou Shengping , Kijlstra Aize , Yang Peizeng 
Published: January 2016

AbstractSeveral modulatory factors in the TLR signaling pathway including IRF3, IRF7, IRF8, TRIM20, MYD88 and NF-κB1 have been associated with autoimmune disease. In this study, we investigated the association of 13 SNPs for these genes with Behçet’s disease (BD) and Vogt-Koyanagi-Harada (VKH) syndrome using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assay. Haplotype and linkage disequilibrium (LD) analysis were performed by Haploview4.2. IRF8 mRNA expression and cytokine production was tested by real-time PCR and ELISA. Two SNPs near IRF8 were associated with BD (for rs17445836 GG genotype, Pc = 9.56 × 10−8, OR = 2.044; for rs11642873 AA genotype, Pc = 9.24 × 10−7, OR = 1.776). No significant association was found for the 13 SNPs tested with VKH syndrome. Haplotype analysis of the two positive SNPs revealed that the AG haplotype was significantly increased in BD patients (Pc = 2.60 × 10−8, OR = 1.646). Functional studies revealed an increased mRNA expression of IRF8 and IFN-γ production and a decreased production of IL-10 in rs17445836 carriers with the GG genotype. Increased expression of IRF8 as well as IFN-γ production and a decreased production of IL-10 were found in individuals carrying the rs11642873/AA genotype. In conclusion, this study indicates that IRF8 may contribute to the genetic susceptibility of BD by regulating IRF8 expression and cytokine production.
Experience-independent sex differences in newborn macaques: Females are more social than males
Authors: Simpson Elizabeth A. , Nicolini Ylenia , Shetler Melissa , Suomi Stephen J. , Ferrari Pier F. , Paukner Annika 
Published: January 2016

AbstractHuman females exhibit greater social interest and skills relative to males, appearing in infancy, suggesting biological roots; however, male and female infants may be treated differently, potentially causing or amplifying sex differences. Here, we tested whether sex differences in social motivation emerge in infant monkeys (n = 48) reared in a controlled postnatal environment. Compared to males, females at 2–3 weeks looked more at conspecifics’ faces (d = 0.65), especially the eyes (d = 1.09) and at 4–5 weeks exhibited more affiliative behaviors (d = 0.64), including gesturing, looking and proximity to familiar and unfamiliar human caretakers. In sum, converging evidence from humans and monkeys suggests that female infants are more social than males in the first weeks of life and that such differences may arise independent of postnatal experience. Individual differences in social interest have wide-ranging developmental consequences, impacting infants’ social interaction quality and opportunities for learning. Understanding the evolution of sex differences and their developmental emergence is necessary to best support infants with varying levels of sociality.
detectMITE: A novel approach to detect miniature inverted repeat transposable elements in genomes
Authors: Ye Congting , Ji Guoli , Liang Chun 
Published: January 2016

AbstractMiniature inverted repeat transposable elements (MITEs) are prevalent in eukaryotic genomes, including plants and animals. Classified as a type of non-autonomous DNA transposable elements, they play important roles in genome organization and evolution. Comprehensive and accurate genome-wide detection of MITEs in various eukaryotic genomes can improve our understanding of their origins, transposition processes, regulatory mechanisms and biological relevance with regard to gene structures, expression and regulation. In this paper, we present a new MATLAB-based program called detectMITE that employs a novel numeric calculation algorithm to replace conventional string matching algorithms in MITE detection, adopts the Lempel-Ziv complexity algorithm to filter out MITE candidates with low complexity and utilizes the powerful clustering program CD-HIT to cluster similar MITEs into MITE families. Using the rice genome as test data, we found that detectMITE can more accurately, comprehensively and efficiently detect MITEs on a genome-wide scale than other popular MITE detection tools. Through comparison with the potential MITEs annotated in Repbase, the widely used eukaryotic repeat database, detectMITE has been shown to find known and novel MITEs with a complete structure and full-length copies in the genome. detectMITE is an open source tool (https://sourceforge.net/projects/detectmite).
Association of toll-like receptor 3 polymorphism rs3775291 with age-related macular degeneration: a systematic review and meta-analysis
Authors: Ma Li , Tang Fang Yao , Chu Wai Kit , Young Alvin L. , Brelen Marten E. , Pang Chi Pui , Chen Li Jia 
Published: January 2016

AbstractAssociation of a polymorphism rs3775291 in the toll-like receptor 3 (TLR3) gene with age-related macular degeneration (AMD) had been investigated intensively, with variable results across studies. Here we conducted a meta-analysis to verify the effect of rs3775291 on AMD. We searched for genetic association studies published in PubMed, EMBASE and Web of Science from start dates to March 10, 2015. Totally 235 reports were retrieved and 9 studies were included for meta-analysis, involving 7400 cases and 13579 controls. Summary odds ratios (ORs) with 95% confidence intervals (CIs) for alleles and genotypes were estimated. TLR3 rs3775291 was associated with both geographic atrophy (GA) and neovascular AMD (nAMD), with marginally significant pooled-P values. Stratification analysis by ethnicity indicated that rs3775291 was associated with all forms of AMD, GA and nAMD only in Caucasians (OR = 0.87, 0.78 and 0.77, respectively, for the TT genotype) but not in East Asians. However, the associations could not withstand Bonferroni correction. This meta-analysis has thus revealed suggestive evidence for TLR3 rs3775291 as an associated marker for AMD in Caucasians but not in Asians. This SNP may have only a small effect on AMD susceptibility. Further studies in larger samples are warranted to confirm its role.
Growing GaN LEDs on amorphous SiC buffer with variable C/Si compositions
Authors: Cheng Chih-Hsien , Tzou An-Jye , Chang Jung-Hung , Chi Yu-Chieh , Lin Yung-Hsiang , Shih Min-Hsiung , Lee Chao-Kuei , Wu Chih-I , Kuo Hao-Chung , Chang Chun-Yen , Lin Gong-Ru 
Published: January 2016

AbstractThe epitaxy of high-power gallium nitride (GaN) light-emitting diode (LED) on amorphous silicon carbide (a-SixC1−x) buffer is demonstrated. The a-SixC1−x buffers with different nonstoichiometric C/Si composition ratios are synthesized on SiO2/Si substrate by using a low-temperature plasma enhanced chemical vapor deposition. The GaN LEDs on different SixC1−x buffers exhibit different EL and C-V characteristics because of the extended strain induced interfacial defects. The EL power decays when increasing the Si content of SixC1−x buffer. The C-rich SixC1−x favors the GaN epitaxy and enables the strain relaxation to suppress the probability of Auger recombination. When the SixC1−x buffer changes from Si-rich to C-rich condition, the EL peak wavelengh shifts from 446 nm to 450 nm. Moreover, the uniform distribution contour of EL intensity spreads between the anode and the cathode because the traping density of the interfacial defect gradually reduces. In comparison with the GaN LED grown on Si-rich SixC1−x buffer, the device deposited on C-rich SixC1−x buffer shows a lower turn-on voltage, a higher output power, an external quantum efficiency and an efficiency droop of 2.48 V, 106 mW, 42.3% and 7%, respectively.
Identification of a rhodopsin gene mutation in a large family with autosomal dominant retinitis pigmentosa
Authors: Yu Xinping , Shi Wei , Cheng Lulu , Wang Yanfang , Chen Ding , Hu Xuting , Xu Jinling , Xu Limin , Wu Yaming , Qu Jia , Gu Feng 
Published: January 2016

AbstractRetinitis pigmentosa (RP) is a genetically highly heterogeneous retinal disease and one of the leading causes of blindness in the world. Next-generation sequencing technology has enormous potential for determining the genetic etiology of RP. We sought to identify the underlying genetic defect in a 35-year-old male from an autosomal-dominant RP family with 14 affected individuals. By capturing next-generation sequencing (CNGS) of 144 genes associated with retinal diseases, we identified eight novel DNA variants; however, none of them cosegregated for all the members of the family. Further analysis of the CNGS data led to identification of a recurrent missense mutation (c.403C > T, p.R135W) in the rhodopsin (RHO) gene, which cosegregated with all affected individuals in the family and was not observed in any of the unaffected family members. The p.R135W mutation has a reference single nucleotide polymorphism (SNP) ID (rs104893775) and it appears to be responsible for the disease in this large family. This study highlights the importance of examining NGS data with reference SNP IDs. Thus, our study is important for data analysis of NGS-based clinical genetic diagnoses.
Effect of simulated tillage on microbial autotrophic CO2 fixation in paddy and upland soils
Authors: Ge Tida , Wu Xiaohong , Liu Qiong , Zhu Zhenke , Yuan Hongzhao , Wang Wei , Whiteley A. S. , Wu Jinshui 
Published: January 2016

AbstractTillage is a common agricultural practice affecting soil structure and biogeochemistry. To evaluate how tillage affects soil microbial CO2 fixation, we incubated and continuously labelled samples from two paddy soils and two upland soils subjected to simulated conventional tillage (CT) and no-tillage (NT) treatments. Results showed that CO2 fixation (14C-SOC) in CT soils was significantly higher than in NT soils. We also observed a significant, soil type- and depth-dependent effect of tillage on the incorporation rates of labelled C to the labile carbon pool. Concentrations of labelled C in the carbon pool significantly decreased with soil depth, irrespective of tillage. Additionally, quantitative PCR assays revealed that for most soils, total bacteria and cbbL-carrying bacteria were less abundant in CT versus NT treatments and tended to decrease in abundance with increasing depth. However, specific CO2 fixation activity was significantly higher in CT than in NT soils, suggesting that the abundance of cbbL-containing bacteria may not always reflect their functional activity. This study highlights the positive effect of tillage on soil microbial CO2 fixation and the results can be readily applied to the development of sustainable agricultural management.
From phenotype to genotype in complex brain networks
Authors: Zanin Massimiliano , Correia Marco , Sousa Pedro A. C. , Cruz Jorge 
Published: January 2016

AbstractGenerative models are a popular instrument for illuminating the relationships between the hidden variables driving the growth of a complex network and its final topological characteristics, a process known as the “genotype to phenotype problem”. However, the definition of a complete methodology encompassing all stages of the analysis and in particular the validation of the final model, is still an open problem. We here discuss a framework that allows to quantitatively optimise and validate each step of the model creation process. It is based on the execution of a classification task and on estimating the additional precision provided by the modelled genotype. This encompasses the three main steps of the model creation, namely the selection of topological features, the optimisation of the parameters of the generative model and the validation of the obtained results. We provide a minimum requirement for a generative model to be useful, prescribing the function mapping genotype to phenotype to be non-monotonic; and we further show how a previously published model does not fulfil such condition, casting doubts on its fitness for the study of neurological disorders. The generality of such framework guarantees its applicability beyond neuroscience, like the emergence of social or technological networks.
Study of Arsenic Sulfide in Solid Tumor Cells Reveals Regulation of Nuclear Factors of Activated T-cells by PML and p53
Authors: Ding Wenping , Tong Yingying , Zhang Xiuli , Pan Minggui , Chen Siyu 
Published: January 2016

AbstractArsenic sulfide (AS) has excellent cytotoxic activity in acute promyelocytic leukemia (APL) but its activity in solid tumors remains to be explored. Here we show that AS and cyclosporine A (CsA) exerted synergistic inhibitory effect on cell growth and c-Myc expression in HCT116 cells. AS inhibited the expression of PML, c-Myc, NFATc1, NFATc3 and NFATc4, while stimulating the expression of p53 and NFATc2. Knockdown of PML reduced NFATc1, NFATc2, NFATc3 and NFATc4 expression while overexpression of p53 stimulated NFATc2-luciferase activity that was further augmented by AS by binding to a set of p53 responsive elements (PREs) on the NFATc2 promoter. Additionally, overexpression of p53 suppressed NFATc3 and NFATc4. Reciprocally, NFATc3 knockdown enhanced p53 while reducing MDM2 expression indicating that NFATc3 is a negative regulator of p53 while a positive regulator of MDM2, consistent with its tumor-promoting property as knockdown of NFATc3 retarded cell growth in vitro and tumor growth in xenograft. In patients with colon cancer, tumor expression of NFATc2 correlated with superior survival, while nuclear NFATc1 with inferior survival. These results indicate that AS differentially regulates NFAT pathway through PML and p53 and reveal an intricate reciprocal regulatory relationship between NFAT proteins and p53 pathway.
Membrane omega-3 fatty acids modulate the oligomerisation kinetics of adenosine A2A and dopamine D2 receptors
Authors: Guixà-González Ramon , Javanainen Matti , Gómez-Soler Maricel , Cordobilla Begoña , Domingo Joan Carles , Sanz Ferran , Pastor Manuel , Ciruela Francisco , Martinez-Seara Hector , Selent Jana 
Published: January 2016

AbstractMembrane levels of docosahexaenoic acid (DHA), an essential omega-3 polyunsaturated fatty acid (ω-3 PUFA), are decreased in common neuropsychiatric disorders. DHA modulates key cell membrane properties like fluidity, thereby affecting the behaviour of transmembrane proteins like G protein-coupled receptors (GPCRs). These receptors, which have special relevance for major neuropsychiatric disorders have recently been shown to form dimers or higher order oligomers and evidence suggests that DHA levels affect GPCR function by modulating oligomerisation. In this study, we assessed the effect of membrane DHA content on the formation of a class of protein complexes with particular relevance for brain disease: adenosine A2A and dopamine D2 receptor oligomers. Using extensive multiscale computer modelling, we find a marked propensity of DHA for interaction with both A2A and D2 receptors, which leads to an increased rate of receptor oligomerisation. Bioluminescence resonance energy transfer (BRET) experiments performed on living cells suggest that this DHA effect on the oligomerisation of A2A and D2 receptors is purely kinetic. This work reveals for the first time that membrane ω-3 PUFAs play a key role in GPCR oligomerisation kinetics, which may have important implications for neuropsychiatric conditions like schizophrenia or Parkinson’s disease.
In silico functional dissection of saturation mutagenesis: Interpreting the relationship between phenotypes and changes in protein stability, interactions and activity
Authors: Pires Douglas E. V. , Chen Jing , Blundell Tom L. , Ascher David B. 
Published: January 2016

AbstractDespite interest in associating polymorphisms with clinical or experimental phenotypes, functional interpretation of mutation data has lagged behind generation of data from modern high-throughput techniques and the accurate prediction of the molecular impact of a mutation remains a non-trivial task. We present here an integrated knowledge-driven computational workflow designed to evaluate the effects of experimental and disease missense mutations on protein structure and interactions. We exemplify its application with analyses of saturation mutagenesis of DBR1 and Gal4 and show that the experimental phenotypes for over 80% of the mutations correlate well with predicted effects of mutations on protein stability and RNA binding affinity. We also show that analysis of mutations in VHL using our workflow provides valuable insights into the effects of mutations and their links to the risk of developing renal carcinoma. Taken together the analyses of the three examples demonstrate that structural bioinformatics tools, when applied in a systematic, integrated way, can rapidly analyse a given system to provide a powerful approach for predicting structural and functional effects of thousands of mutations in order to reveal molecular mechanisms leading to a phenotype. Missense or non-synonymous mutations are nucleotide substitutions that alter the amino acid sequence of a protein. Their effects can range from modifying transcription, translation, processing and splicing, localization, changing stability of the protein, altering its dynamics or interactions with other proteins, nucleic acids and ligands, including small molecules and metal ions. The advent of high-throughput techniques including sequencing and saturation mutagenesis has provided large amounts of phenotypic data linked to mutations. However, one of the hurdles has been understanding and quantifying the effects of a particular mutation and how they translate into a given phenotype. One approach to overcome this is to use robust, accurate and scalable computational methods to understand and correlate structural effects of mutations with disease.
Comprehensive analyses of how tubule occlusion and advanced glycation end-products diminish strength of aged dentin
Authors: Shinno Yuko , Ishimoto Takuya , Saito Mitsuru , Uemura Reo , Arino Masumi , Marumo Keishi , Nakano Takayoshi , Hayashi Mikako 
Published: January 2016

AbstractIn clinical dentistry, since fracture is a major cause of tooth loss, better understanding of mechanical properties of teeth structures is important. Dentin, the major hard tissue of teeth, has similar composition to bone. In this study, we investigated the mechanical properties of human dentin not only in terms of mineral density but also using structural and quality parameters as recently accepted in evaluating bone strength. Aged crown and root dentin (age ≥ 40) exhibited significantly lower flexural strength and toughness than young dentin (age < 40). Aged dentin, in which the dentinal tubules were occluded with calcified material, recorded the highest mineral density; but showed significantly lower flexural strength than young dentin. Dentin with strong alignment of the c-axis in hydroxyapatite exhibited high fracture strength, possibly because the aligned apatite along the collagen fibrils may reinforce the intertubular dentin. Aged dentin, showing a high advanced glycation end-products (AGEs) level in its collagen, recorded low flexural strength. We first comprehensively identified significant factors, which affected the inferior mechanical properties of aged dentin. The low mechanical strength of aged dentin is caused by the high mineral density resulting from occlusion of dentinal tubules and accumulation of AGEs in dentin collagen.