bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of oxidative stress and subsequent induction of apoptosis and endoplasmic reticulum stress allows citral to decrease cancer cell proliferation
Authors: Kapur Arvinder , Felder Mildred , Fass Lucas , Kaur Justanjot , Czarnecki Austin , Rathi Kavya , Zeng San , Osowski Kathryn Kalady , Howell Colin , Xiong May P. , Whelan Rebecca J. , Patankar Manish S. 
Published: June 2016

AbstractThe monoterpenoid, citral, when delivered through PEG-b-PCL nanoparticles inhibits in vivo growth of 4T1 breast tumors. Here, we show that citral inhibits proliferation of multiple human cancer cell lines. In p53 expressing ECC-1 and OVCAR-3 but not in p53-deficient SKOV-3 cells, citral induces G1/S cell cycle arrest and apoptosis as determined by Annexin V staining and increased cleaved caspase3 and Bax and decreased Bcl-2. In SKOV-3 cells, citral induces the ER stress markers CHOP, GADD45, EDEM, ATF4, Hsp90, ATG5 and phospho-eIF2α. The molecular chaperone 4-phenylbutyric acid attenuates citral activity in SKOV-3 but not in ECC-1 and OVCAR-3 cells. In p53-expressing cells, citral increases phosphorylation of serine-15 of p53. Activation of p53 increases Bax, PUMA and NOXA expression. Inhibition of p53 by pifithrin-α, attenuates citral-mediated apoptosis. Citral increases intracellular oxygen radicals and this leads to activation of p53. Inhibition of glutathione synthesis by L-buthionine sulfoxamine increases potency of citral. Pretreatment with N-acetylcysteine decreases phosphorylation of p53 in citral-treated ECC-1 and OVCAR-3. These results define a p53-dependent and in the absence of p53, ER stress-dependent mode of action of citral. This study indicates that citral in PEG-b-PCL nanoparticle formulation should be considered for treatment of breast and other tumors.
Association-heterogeneity mapping identifies an Asian-specific association of the GTF2I locus with rheumatoid arthritis
Authors: Kim Kwangwoo , Bang So-Young , Ikari Katsunori , Yoo Dae Hyun , Cho Soo-Kyung , Choi Chan-Bum , Sung Yoon-Kyoung , Kim Tae-Hwan , Jun Jae-Bum , Kang Young Mo , Suh Chang-Hee , Shim Seung-Cheol , Lee Shin-Seok , Lee Jisoo , Chung Won Tae , Kim Seong-Kyu , Choe Jung-Yoon , Momohara Shigeki , Taniguchi Atsuo , Yamanaka Hisashi , Nath Swapan K. , Lee Hye-Soon , Bae Sang-Cheol 
Published: June 2016

AbstractConsiderable sharing of disease alleles among populations is well-characterized in autoimmune disorders (e.g., rheumatoid arthritis), but there are some exceptional loci showing heterogenic association among populations. Here we investigated genetic variants with distinct effects on the development of rheumatoid arthritis in Asian and European populations. Ancestry-related association heterogeneity was examined using Cochran’s homogeneity tests for the disease association data from large Asian (n = 14,465; 9,299 discovery subjects and 5,166 validation subjects; 4 collections) and European (n = 45,790; 11 collections) rheumatoid arthritis case-control cohorts with Immunochip and genome-wide SNP array data. We identified significant heterogeneity between the two ancestries for the common variants in the GTF2I locus (PHeterogeneity = 9.6 × 10−9 at rs73366469) and showed that this heterogeneity was due to an Asian-specific association effect (ORMeta = 1.37 and PMeta = 4.2 × 10−13 in Asians; ORMeta = 1.00 and PMeta = 1.00 in Europeans). Trans-ancestral comparison and bioinfomatics analysis revealed a plausibly causal or disease-variant-tagging SNP (rs117026326; in linkage disequilibrium with rs73366469), whose minor allele is common in Asians but rare in Europeans. In conclusion, we identified largest-ever effect on Asian rheumatoid arthritis across human non-HLA regions at GTF2I by heterogeneity mapping followed by replication studies, and pinpointed a possible causal variant.
Design, biological evaluation and 3D QSAR studies of novel dioxin-containing pyrazoline derivatives with thiourea skeleton as selective HER-2 inhibitors
Authors: Yang Bing , Yang Yu-Shun , Yang Na , Li Guigen , Zhu Hai-Liang 
Published: June 2016

AbstractA series of novel dioxin-containing pyrazoline derivatives with thiourea skeleton have been designed, synthesized and evaluated for their EGFR/HER-2 inhibitory and anti-proliferation activities. A majority of them displayed selective HER-2 inhibitory activity against EGFR inhibitory activity. Compound C20 displayed the most potent activity against HER-2 and MDA-MB-453 human breast cancer cell line (IC50 = 0.03 μM and GI50 = 0.15 μM), being slightly more potent than the positive control Erlotinib (IC50 = 0.16 μM and GI50 = 1.56 μM) and comparable with Lapatinib (IC50 = 0.01 μM and GI50 = 0.03 μM). It is a more exciting result that C20 was over 900 times more potent against HER-2 than against EGFR while this value was 0.19 for Erlotinib and 1.00 for Lapatinib, indicating high selectivity. The results of docking simulation indicate that the dioxin moiety occupied the exit of the active pocket and pushed the carbothioamide deep into the active site. QSAR models have been built with activity data and binding conformations to begin our work in this paper as well as to provide a reliable tool for reasonable design of EGFR/HER-2 inhibitors in future.
(±)-Japonones A and B, two pairs of new enantiomers with anti-KSHV activities from Hypericum japonicum
Authors: Hu Linzhen , Zhu Hucheng , Li Lei , Huang Jinfeng , Sun Weiguang , Liu Junjun , Li Hua , Luo Zengwei , Wang Jianping , Xue Yongbo , Zhang Yu , Zhang Yonghui 
Published: June 2016

AbstractTwo pairs of new enantiomers with unusual 5,5-spiroketal cores, termed (±)-japonones A and B [(±)-1and (±)-2], were obtained fromHypericum japonicumThunb. The absolute configurations of (±)-1and (±)-2were characterized by extensive analyses of spectroscopic data and calculated electronic circular dichroism (ECD) spectra, the application of modified Mosher’s methods and the assistance of quantum chemical predictions (QCP) of13C NMR chemical shifts. Among these metabolites, (+)-1exhibited some inhibitory activity on Kaposi’s sarcoma associated herpesvirus (KSHV). Virtual screening of (±)-1and (±)-2were conducted using the Surflex-Dock module in the Sybyl software and (+)-1exhibited ability to bind with ERK to form key interactions with residues Lys52, Pro56, Ile101, Asp165, Gly167 and Val99.
Cardiac arrest triggers hippocampal neuronal death through autophagic and apoptotic pathways
Authors: Cui Derong , Shang Hanbing , Zhang Xiaoli , Jiang Wei , Jia Xiaofeng 
Published: June 2016

Abstract
The mechanism of neuronal death induced by ischemic injury remains unknown. We investigated whether autophagy and p53 signaling played a role in the apoptosis of hippocampal neurons following global cerebral ischemia-reperfusion (I/R) injury, in a rat model of 8-min asphyxial cardiac arrest (CA) and resuscitation. Increased autophagosome numbers, expression of lysosomal cathepsin B, cathepsin D, Beclin-1 and microtubule-associated protein light chain 3 (LC3) suggested autophagy in hippocampal cells. The expression of tumor suppressor protein 53 (p53) and its target genes: Bax, p53-upregulated modulator of apoptosis (PUMA) and damage-regulated autophagy modulator (DRAM) were upregulated following CA. The p53-specific inhibitor pifithrin-α (PFT-α) significantly reduced the expression of pro-apoptotic proteins (Bax and PUMA) and autophagic proteins (LC3-II and DRAM) that generally increase following CA. PFT-α also reduced hippocampal neuronal damage following CA. Similarly, 3-methyladenine (3-MA), which inhibits autophagy and bafilomycin A1 (BFA), which inhibits lysosomes, significantly inhibited hippocampal neuronal damage after CA. These results indicate that CA affects both autophagy and apoptosis, partially mediated by p53. Autophagy plays a significant role in hippocampal neuronal death induced by cerebral I/R following asphyxial-CA.
Detachment of secondary dendrite arm in a directionally solidified Sn-Ni peritectic alloy under deceleration growth condition
Authors: Peng Peng , Li Xinzhong , Li Jiangong , Su Yanqing , Guo Jingjie , Fu Hengzhi 
Published: June 2016

AbstractIn order to better understand the detachment mechanism of secondary dendrite arm during peritectic solidification, the detachment of secondary dendrite arm from the primary dendrite arms in directionally solidified Sn-36at.%Ni peritectic alloys is investigated at different deceleration rates. Extensive detachment of secondary dendrite arms from primary stem is observed below peritectic reaction temperature TP. And an analytical model is established to characterize the detachment process in terms of the secondary dendrite arm spacing λ2, the root radius of detached arms and the specific surface area (SV) of dendrites. It is found that the detachment mechanism is caused by not only curvature difference between the tips and roots of secondary branches, but also that between the thicker secondary branches and the thinner ones. Besides, this detachment process is significantly accelerated by the temperature gradient zone melting (TGZM) effect during peritectic solidification. It is demonstrated that the reaction constant (f) which is used to characterize the kinetics of peritectic reaction is crucial for the determination of the detachment process. The value of f not only changes with growth rate but also with solidification time at a given deceleration rate. In conclusion, these findings help the better understanding of the detachment mechanism.
E2F and GATA switches turn off WD repeat domain 77 expression in differentiating cells
Authors: Yu Min , Wang Ulrica , Wang Zhengxin 
Published: June 2016

WDR77 (WD repeat domain 77) is expressed during earlier lung development when cells are rapidly proliferating, but is absent from adult lung. It is re-activated during lung tumorigenesis and is essential for lung cancer cell proliferation. Signalling pathways/molecules that control WDR77 gene expression are unknown. Promoter mapping, gel shift assay and ChIP revealed that the WDR77 promoter contains bona fide response elements for E2F and GATA transcriptional factors as demonstrated in prostate cancer, lung cancer and erythroid cells, as well as in mouse lung tissues. The WDR77 promoter is transactivated by E2F1, E2F3, GATA1 and GATA6, but suppressed by E2F6, GATA1 and GATA3 in prostate cancer PC3 cells. WDR77 expression is associated with E2F1, E2F3, GATA2 and GATA6 occupancy on the WDR77 gene, whereas, in contrast, E2F6, GATA1 and GATA3 occupancy is associated with the loss of WDR77 expression during erythroid maturation and lung development. More importantly, the loss of WDR77 expression that results from E2F and GATA switches is required for cellular differentiation of erythroid and lung epithelial cells. In contrast, lung cancer cells avoid post-mitotic differentiation by sustaining WDR77 expression. Altogether, the present study provides a novel molecular mechanism by which WDR77 is regulated during erythroid and lung development and lung tumorigenesis.
Compact ECDSA engine for IoT applications
Authors: Yalçin T. 
Published: June 2016

Security problems introduced with rapid increase in deployment of Internet‐of‐Things devices can be overcome only with lightweight cryptographic schemes and modules. A compact prime field (GF(p)) elliptic curve digital signature algorithm (ECDSA) engine suitable for use in such applications is presented. Generic architecture of the engine makes it suitable for other elliptic curve (EC) based schemes (EC Diffie–Hellman key exchange, EC integrated encryption, EC factoring etc.) with slight modifications. The presented engine is composed of a simple microcoded controller and application‐specific processing units. It can work with ECs of up to 256 bits, while 160‐bit ECDSA signature generation takes 490 K cycles. The engine is implemented as an intellectual property (IP) in a 180 nm process. However, its architecture allows it to be implemented on any application specific integrated circuit (ASIC) or FPGA platform with dual‐port memory support. In view of its gate count of 11,366 gate equivalents, the presented work is the most compact ECDSA engine with capability for a wide range of curves and different applications.
Constructing Space for Dissent in War: The Bombing Restriction Committee, 1941–1945
Authors: Overy Richard 
Published: June 2016

Abstract
The prevailing view of the British public’s response to the RAF bomber offensive during the Second World War suggests that there was widespread and even enthusiastic support for the bombing aside from a small number of prominent individuals, chiefly the writer Vera Brittain and the Bishop of Chichester, George Bell. This article challenges the view that there was little overt dissent over the bombing campaign by looking at the origins, activity and impact of the Bombing Restriction Committee, the title given in 1942 to the Committee for the Abolition of Night Bombing founded in August 1941. The Committee undertook a wide range of activity in protest first against night-bombing, and then more generally against the RAF’s shift to area bombing in 1941–2. The article examines the network of supporters that the committee developed and the nature and extent of its propaganda, and addresses the question of why the protest against a major aspect of British strategy was allowed to continue throughout the war without serious interference. The result suggests that the ideal of a ‘democratic consensus’ in Britain was not realised on this issue; instead it can be argued that official tolerance for protest demonstrated more clearly Britain’s democratic credentials, while it allowed the Committee to keep alive the evolving humanitarian concern of sections of pre-war British society, and to sustain those concerns on into the nuclear age.
Implementation and performance of FDPS: a framework for developing parallel particle simulation codes
Authors: Iwasawa Masaki , Tanikawa Ataru , Hosono Natsuki , Nitadori Keigo , Muranushi Takayuki , Makino Junichiro 
Published: June 2016

Abstract
We present the basic idea, implementation, measured performance, and performance model of FDPS (Framework for Developing Particle Simulators). FDPS is an application-development framework which helps researchers to develop simulation programs using particle methods for large-scale distributed-memory parallel supercomputers. A particle-based simulation program for distributed-memory parallel computers needs to perform domain decomposition, exchange of particles which are not in the domain of each computing node, and gathering of the particle information in other nodes which are necessary for interaction calculation. Also, even if distributed-memory parallel computers are not used, in order to reduce the amount of computation, algorithms such as the Barnes–Hut tree algorithm or the Fast Multipole Method should be used in the case of long-range interactions. For short-range interactions, some methods to limit the calculation to neighbor particles are required. FDPS provides all of these functions which are necessary for efficient parallel execution of particle-based simulations as “templates,” which are independent of the actual data structure of particles and the functional form of the particle–particle interaction. By using FDPS, researchers can write their programs with the amount of work necessary to write a simple, sequential and unoptimized program of O(N2) calculation cost, and yet the program, once compiled with FDPS, will run efficiently on large-scale parallel supercomputers. A simple gravitational N-body program can be written in around 120 lines. We report the actual performance of these programs and the performance model. The weak scaling performance is very good, and almost linear speed-up was obtained for up to the full system of the K computer. The minimum calculation time per timestep is in the range of 30 ms (N = 107) to 300 ms (N = 109). These are currently limited by the time for the calculation of the domain decomposition and communication necessary for the interaction calculation. We discuss how we can overcome these bottlenecks.
Efficient cardinality estimation for k-mers in large DNA sequencing data sets
Authors: Irber Luiz C. , Brown C. Titus 
Published: June 2016

AbstractWe present an open implementation of the HyperLogLog cardinality estimation sketch for counting fixed-length substrings of DNA strings (“k-mers”).The HyperLogLog sketch implementation is in C++ with a Python interface, and is distributed as part of the khmer software package. khmer is freely available fromhttps://github.com/dib-lab/khmerunder a BSD License. The features presented here are included in version 1.4 and later.
Daisy-chain gene drives for the alteration of local populations
Authors: Noble Charleston , Min John , Olejarz Jason , Buchthal Joanna , Chavez Alejandro , Smidler Andrea L. , DeBenedictis Erika A. , Church George M. , Nowak Martin A. , Esvelt Kevin M. 
Published: June 2016

AbstractRNA-guided gene drive elements could address many ecological problems by altering the traits of wild organisms, but the likelihood of global spread tremendously complicates ethical development and use. Here we detail a localized form of CRISPR-based gene drive composed of genetic elements arranged in a daisy-chain such that each element drives the next. “Daisy drive” systems can duplicate any effect achievable using an equivalent global drive system, but their capacity to spread is limited by the successive loss of non-driving elements from the base of the chain. Releasing daisy drive organisms constituting a small fraction of the local wild population can drive a useful genetic element to local fixation for a wide range of fitness parameters without resulting in global spread. We additionally report numerous highly active guide RNA sequences sharing minimal homology that may enable evolutionary stable daisy drive as well as global CRISPR-based gene drive. Daisy drives could simplify decision-making and promote ethical use by enabling local communities to decide whether, when, and how to alter local ecosystems.Author’s Summary‘Global’ gene drive systems based on CRISPR are likely to spread to every population of the target species, hampering safe and ethical use. ‘Daisy drive’ systems offer a way to alter the traits of only local populations in a temporary manner. Because they can exactly duplicate the activity of any global CRISPR-based drive at a local level, daisy drives may enable safe field trials and empower local communities to make decisions concerning their own shared environments.For more details and an animation intended for a general audience, see the summary atSculpting Evolution.
A Common Class of Transcripts with 5′-Intron Depletion, Distinct Early Coding Sequence Features, and N1-Methyladenosine Modification
Authors: Cenik Can , Chua Hon Nian , Singh Guramrit , Akef Abdalla , Snyder Michael P , Palazzo Alexander F. , Moore Melissa J , Roth Frederick P 
Published: June 2016

AbstractIntrons are found in 5’ untranslated regions (5’UTRs) for 35% of all human transcripts. These 5’UTR introns are not randomly distributed: genes that encode secreted, membrane-bound and mitochondrial proteins are less likely to have them. Curiously, transcripts lacking 5’UTR introns tend to harbor specific RNA sequence elements in their early coding regions. To model and understand the connection between coding-region sequence and 5’UTR intron status, we developed a classifier that can predict 5’UTR intron status with >80% accuracy using only sequence features in the early coding region. Thus, the classifier identifies transcripts with5’ proximal-intron-minus-like-coding regions (“5IM” transcripts). Unexpectedly, we found that the early coding sequence features defining 5IM transcripts are widespread, appearing in 21% of all human RefSeq transcripts. The 5IM class of transcripts is enriched for non-AUG start codons, more extensive secondary structure both preceding the start codon and near the 5’ cap, greater dependence on eIF4E for translation, and association with ER-proximal ribosomes. 5IM transcripts are bound by the Exon Junction Complex (EJC) at non-canonical 5’ proximal positions. Finally, N1-methyladenosines are specifically enriched in the early coding regions of 5IM transcripts. Taken together, our analyses point to the existence of a distinct 5IM class comprising ∼20% of human transcripts. This class is defined by depletion of 5’ proximal introns, presence of specific RNA sequence features associated with low translation efficiency, N1-methyladenosines in the early coding region, and enrichment for non-canonical binding by the Exon Junction Complex.
Uplift and erosion of genomic islands with standing genetic variation
Authors: Hether Tyler D. 
Published: June 2016

AbstractDetails of the processes that generate biological diversity have long been of interest to evolutionary biologists. A common theme in nature is diversification via divergent selection with gene flow. Empirical studies on this topic find variable genetic differentiation throughout the genome, that genetic differentiation is non-randomly distributed, and that loci of adaptive significance are often found clustered together within “genomic islands of divergence”. Theoretical models based on new mutations show how these genomic islands can arise and grow as a result of a complex interaction of various evolutionary and genic processes. In the current study, I ask if such genomic islands can alternatively arise from divergent selection from standing genetic variation and I tested this using a simple two locus model of selection. There are numerous ways in which standing genetic variation can be partitioned (e.g., between alleles, between loci, and between populations) and I tested which of these scenarios can give rise to an island pattern compared to no genomic differentiation or complete genomic differentiation. I found that divergent selection, even without reciprocal gene exchange between populations, following a bout of admixture can relatively quickly produce an island pattern. Moreover, I found two pathways in which islands can form from divergence from standing variation: 1) through the build up of islands and 2) through the breakdown of larger, genome-wide differentiation. Lastly, similar to new mutation theory, I found that the frequency of recombination is an important determinant of island formation from standing genetic variation such that mating behavior of a species (e.g., facultative or obligate sexual) can impact the likelihood of island formation.