bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rationale and design of ASSAF‐K (A study of the safety and efficacy of anticoagulant therapy in the treatment of atrial fibrillation in Kanagawa)
Authors: Hatori Yutaka , Sakai Hiroyuki , Kunishima Tomoyuki , Hatori Nobuo , Chen Lin , Ishigami Tomoaki , Satoh Naoki ,   ASSAF‐K Investigators
Published: August 2016

AbstractBackgroundAtrial fibrillation (AF) is one of the most prevalent cardiac arrhythmias associated with substantially increased risks of ischemic stroke and thromboembolism. Oral anticoagulants (OACs) are the cornerstone of AF management and effectively prevent AF‐related stroke. As new non‐vitamin K antagonist OACs (NOACs) have become available, the landscape of stroke prevention in AF has changed. However, there are considerable gaps between daily clinical practice and current guideline‐based recommendations for anticoagulant therapy in Japan. Consequently, little is known about the real‐world setting and the current use of NOACs, especially by practitioners in Japan.MethodsWe conducted a prospective, observational study in 3847 patients with AF who were enrolled in clinics and hospitals located in Kanagawa Prefecture from September 2013 through March 2015. The participating centers included practitioners (small clinics), medium‐sized hospitals, and university hospitals. The primary endpoints were epidemiologic characteristics, status of treatment with anticoagulants and antiplatelet agents, outcomes, and adverse events, including cerebrovascular disease, bleeding, and death.ResultsThe mean CHADS2 score was 1.81±1.27, the mean CHADS2‐Vasc score was 3.02±1.58, and the mean HAS‐BLED score was 2.23±1.06, respectively. The usage rate of warfarin was 44.2% overall, and the usage rate of NOACs was 33.5%.ConclusionsThe results of the study are expected to serve as the basis for providing clinical practice guidance to healthcare institutions in Japan, with the ultimate goals of better characterizing the appropriate use of OACs and providing clinical decision support to physicians to facilitate the design of appropriate therapeutic strategies and the selection of anticoagulants for the management of AF.
Alzheimer's drug‐development pipeline: 2016
Authors: Cummings Jeffrey , Morstorf Travis , Lee Garam 
Published: August 2016

AbstractBackgroundAlzheimer's disease (AD) is growing in frequency and new therapies are urgently needed.MethodsWe assessed clinicaltrials.gov (accessed 1‐4‐2016) to determine the number and characteristics of trials in phase I, phase II, and phase III for treatment of AD.ResultsThere are currently 24 agents in 36 trials in phase III of AD drug development. Seven of these 24 agents are symptomatic cognitive‐enhancing compounds, and 17 are disease‐modifying treatments (DMTs). Most DMTs address amyloid‐related targets (76%). There are 45 agents in phase II being assessed in 52 clinical trials. Phase II trials include 30 DMTs, with 26 small molecules and 4 immunotherapies. There are 24 agents in the first phase of AD drug development.DiscussionAmyloid is the principal target of late‐stage development programs. There are relatively few agents in clinical trials for AD suggesting a need to amplify the drug discovery ecosystem.
Emergent nanoscale superparamagnetism at oxide interfaces
Authors: Anahory Y. , Embon L. , Li C. J. , Banerjee S. , Meltzer A. , Naren H. R. , Yakovenko A. , Cuppens J. , Myasoedov Y. , Rappaport M. L. , Huber M. E. , Michaeli K. , Venkatesan T. , Ariando  , Zeldov E. 
Published: August 2016

AbstractAtomically sharp oxide heterostructures exhibit a range of novel physical phenomena that are absent in the parent compounds. A prominent example is the appearance of highly conducting and superconducting states at the interface between LaAlO3 and SrTiO3. Here we report an emergent phenomenon at the LaMnO3/SrTiO3 interface where an antiferromagnetic Mott insulator abruptly transforms into a nanoscale inhomogeneous magnetic state. Upon increasing the thickness of LaMnO3, our scanning nanoSQUID-on-tip microscopy shows spontaneous formation of isolated magnetic nanoislands, which display thermally activated moment reversals in response to an in-plane magnetic field. The observed superparamagnetic state manifests the emergence of thermodynamic electronic phase separation in which metallic ferromagnetic islands nucleate in an insulating antiferromagnetic matrix. We derive a model that captures the sharp onset and the thickness dependence of the magnetization. Our model suggests that a nearby superparamagnetic–ferromagnetic transition can be gate tuned, holding potential for applications in magnetic storage and spintronics.
Intermediate magnetization state and competing orders in Dy2Ti2O7 and Ho2Ti2O7
Authors: Borzi R. A. , Gómez Albarracín F. A. , Rosales H. D. , Rossini G. L. , Steppke A. , Prabhakaran D. , Mackenzie A. P. , Cabra D. C. , Grigera S. A. 
Published: August 2016

AbstractAmong the frustrated magnetic materials, spin-ice stands out as a particularly interesting system. Residual entropy, freezing and glassiness, Kasteleyn transitions and fractionalization of excitations in three dimensions all stem from a simple classical Hamiltonian. But is the usual spin-ice Hamiltonian a correct description of the experimental systems? Here we address this issue by measuring magnetic susceptibility in the two most studied spin-ice compounds, Dy2Ti2O7 and Ho2Ti2O7, using a vector magnet. Using these results, and guided by a theoretical analysis of possible distortions to the pyrochlore lattice, we construct an effective Hamiltonian and explore it using Monte Carlo simulations. We show how this Hamiltonian reproduces the experimental results, including the formation of a phase of intermediate polarization, and gives important information about the possible ground state of real spin-ice systems. Our work suggests an unusual situation in which distortions might contribute to the preservation rather than relief of the effects of frustration.
RNF168 and USP10 regulate topoisomerase IIα function via opposing effects on its ubiquitylation
Authors: Guturi Kiran Kumar Naidu , Bohgaki Miyuki , Bohgaki Toshiyuki , Srikumar Tharan , Ng Deborah , Kumareswaran Ramya , El Ghamrasni Samah , Jeon Justin , Patel Parasvi , Eldin Mohamed Saad , Bristow Rob , Cheung Peter , Stewart Grant S. , Raught Brian , Hakem Anne , Hakem Razqallah 
Published: August 2016

AbstractTopoisomerase IIα (TOP2α) is essential for chromosomal condensation and segregation, as well as genomic integrity. Here we report that RNF168, an E3 ligase mutated in the human RIDDLE syndrome, interacts with TOP2α and mediates its ubiquitylation. RNF168 deficiency impairs decatenation activity of TOP2α and promotes mitotic abnormalities and defective chromosomal segregation. Our data also indicate that RNF168 deficiency, including in human breast cancer cell lines, confers resistance to the anti-cancer drug and TOP2 inhibitor etoposide. We also identify USP10 as a deubiquitylase that negatively regulates TOP2α ubiquitylation and restrains its chromatin association. These findings provide a mechanistic link between the RNF168/USP10 axis and TOP2α ubiquitylation and function, and suggest a role for RNF168 in the response to anti-cancer chemotherapeutics that target TOP2.
Relative vascular permeability and vascularity across different regions of the rat nasal mucosa: implications for nasal physiology and drug delivery
Authors: Kumar Niyanta N. , Gautam Mohan , Lochhead Jeffrey J. , Wolak Daniel J. , Ithapu Vamsi , Singh Vikas , Thorne Robert G. 
Published: August 2016

AbstractIntranasal administration provides a non-invasive drug delivery route that has been proposed to target macromolecules either to the brain via direct extracellular cranial nerve-associated pathways or to the periphery via absorption into the systemic circulation. Delivering drugs to nasal regions that have lower vascular density and/or permeability may allow more drug to access the extracellular cranial nerve-associated pathways and therefore favor delivery to the brain. However, relative vascular permeabilities of the different nasal mucosal sites have not yet been reported. Here, we determined that the relative capillary permeability to hydrophilic macromolecule tracers is significantly greater in nasal respiratory regions than in olfactory regions. Mean capillary density in the nasal mucosa was also approximately 5-fold higher in nasal respiratory regions than in olfactory regions. Applying capillary pore theory and normalization to our permeability data yielded mean pore diameter estimates ranging from 13–17 nm for the nasal respiratory vasculature compared to <10 nm for the vasculature in olfactory regions. The results suggest lymphatic drainage for CNS immune responses may be favored in olfactory regions due to relatively lower clearance to the bloodstream. Lower blood clearance may also provide a reason to target the olfactory area for drug delivery to the brain.
Multiscale dispersion-state characterization of nanocomposites using optical coherence tomography
Authors: Schneider Simon , Eppler Florian , Weber Marco , Olowojoba Ganiu , Weiss Patrick , Hübner Christof , Mikonsaari Irma , Freude Wolfgang , Koos Christian 
Published: August 2016

AbstractNanocomposite materials represent a success story of nanotechnology. However, development of nanomaterial fabrication still suffers from the lack of adequate analysis tools. In particular, achieving and maintaining well-dispersed particle distributions is a key challenge, both in material development and industrial production. Conventional methods like optical or electron microscopy need laborious, costly sample preparation and do not permit fast extraction of nanoscale structural information from statistically relevant sample volumes. Here we show that optical coherence tomography (OCT) represents a versatile tool for nanomaterial characterization, both in a laboratory and in a production environment. The technique does not require sample preparation and is applicable to a wide range of solid and liquid material systems. Large particle agglomerates can be directly found by OCT imaging, whereas dispersed nanoparticles are detected by model-based analysis of depth-dependent backscattering. Using a model system of polystyrene nanoparticles, we demonstrate nanoparticle sizing with high accuracy. We further prove the viability of the approach by characterizing highly relevant material systems based on nanoclays or carbon nanotubes. The technique is perfectly suited for in-line metrology in a production environment, which is demonstrated using a state-of-the-art compounding extruder. These experiments represent the first demonstration of multiscale nanomaterial characterization using OCT.
RNA sequencing from neural ensembles activated during fear conditioning in the mouse temporal association cortex
Authors: Cho Jin-Hyung , Huang Ben S. , Gray Jesse M. 
Published: August 2016

AbstractThe stable formation of remote fear memories is thought to require neuronal gene induction in cortical ensembles that are activated during learning. However, the set of genes expressed specifically in these activated ensembles is not known; knowledge of such transcriptional profiles may offer insights into the molecular program underlying stable memory formation. Here we use RNA-Seq to identify genes whose expression is enriched in activated cortical ensembles labeled during associative fear learning. We first establish that mouse temporal association cortex (TeA) is required for remote recall of auditory fear memories. We then perform RNA-Seq in TeA neurons that are labeled by the activity reporter Arc-dVenus during learning. We identify 944 genes with enriched expression in Arc-dVenus+ neurons. These genes include markers of L2/3, L5b, and L6 excitatory neurons but not glial or inhibitory markers, confirming Arc-dVenus to be an excitatory neuron-specific but non-layer-specific activity reporter. Cross comparisons to other transcriptional profiles show that 125 of the enriched genes are also activity-regulated in vitro or induced by visual stimulus in the visual cortex, suggesting that they may be induced generally in the cortex in an experience-dependent fashion. Prominent among the enriched genes are those encoding potassium channels that down-regulate neuronal activity, suggesting the possibility that part of the molecular program induced by fear conditioning may initiate homeostatic plasticity.
Assessing bleeding risk in 4824 Asian patients with atrial fibrillation: The Beijing PLA Hospital Atrial Fibrillation Project
Authors: Guo Yu-tao , Zhang Ye , Shi Xiang-min , Shan Zhao-liang , Wang Chun-jiang , Wang Yu-tang , Chen Yun-dai , Lip Gregory Y. H. 
Published: August 2016

AbstractThe risks of major bleeding and intracranial hemorrhage (ICH) are higher in Asian patients with atrial fibrillation (AF) compared to non-Asians. We aimed to investigate risk factors for bleeding and validate the predictive value of available bleeding risk scores (mOBRI, HEMORR2HAGES, Shireman, HAS-BLED, ATRIA and ORBIT) in a large cohort of Chinese inpatients with AF. Using hospital electronic medical databases, we identified 4824 AF patients (mean age 67 years; 34.9% female) from January 1, 1995 to May 30, 2015, with median (interquartile) in-hospital days of 10 (7–16) days. On multivariate analysis, prior bleeds, vascular disease, anemia, prior stroke and liver dysfunction were independent risk factors of major bleeding (all p < 0.05). C-statistics (95%CI) of the HAS-BLED score were 0.72 (0.65–0.79) for major bleeding events and 0.83 (0.75–0.91) for ICH (all p < 0.001). Compared to other risk scores, the HAS-BLED score was significantly better in predicting major bleeding events (Delong test, all P < 0.05, apart from mOBRI, HEMORR2HAGES) and ICH (all p < 0.05) and additionally, resulted in a net reclassification improvement (NRI) of 17.1–65.5% in predicting major bleeding events and 29.5–67.3% in predicting ICH (all p < 0.05). We conclude that the HAS-BLED score had the best predictive and discriminatory ability for major bleeding and ICH in an Asian/Chinese AF population.
Recent evolution of the salivary mucin MUC7
Authors: Xu Duo , Pavlidis Pavlos , Thamadilok Supaporn , Redwood Emilie , Fox Sara , Blekhman Ran , Ruhl Stefan , Gokcumen Omer 
Published: August 2016

AbstractGenomic structural variants constitute the majority of variable base pairs in primate genomes and affect gene function in multiple ways. While whole gene duplications and deletions are relatively well-studied, the biology of subexonic (i.e., within coding exon sequences), copy number variation remains elusive. The salivary MUC7 gene provides an opportunity for studying such variation, as it harbors copy number variable subexonic repeat sequences that encode for densely O-glycosylated domains (PTS-repeats) with microbe-binding properties. To understand the evolution of this gene, we analyzed mammalian and primate genomes within a comparative framework. Our analyses revealed that (i) MUC7 has emerged in the placental mammal ancestor and rapidly gained multiple sites for O-glycosylation; (ii) MUC7 has retained its extracellular activity in saliva in placental mammals; (iii) the anti-fungal domain of the protein was remodified under positive selection in the primate lineage; and (iv) MUC7 PTS-repeats have evolved recurrently and under adaptive constraints. Our results establish MUC7 as a major player in salivary adaptation, likely as a response to diverse pathogenic exposure in primates. On a broader scale, our study highlights variable subexonic repeats as a primary source for modular evolutionary innovation that lead to rapid functional adaptation.
Idiopathic Choroidal Neovascularization: Intraocular Inflammatory Cytokines and the Effect of Intravitreal Ranibizumab Treatment
Authors: Yin Houfa , Fang Xiaoyun , Ma Jian , Chen Min , Yang Yabo , Guo Shenchao , Chen Zhiqing , Su Zhaoan , Feng Lei , Ye Panpan , Wu Fang , Yin Jinfu 
Published: August 2016

AbstractIdiopathic choroidal neovascularization (ICNV) is a disorder that primarily affecting patients younger than 50 years and can cause severe loss of vision. Choroidal abnormalities, especially choroidal inflammation, have been thought to be involved in the pathophysiology of ICNV. However, the exact pathogenesis of ICNV remains unclear. The aim of our study was investigate the levels of 27 inflammatory cytokines in the aqueous humor of eyes with ICNV and to determine the effect of intravitreal injection of ranibizumab (IVR) on cytokine levels. Significantly higher levels of IL-2, IL-10, IL-15, IL-17, basic FGF and GM-CSF were observed in patients with ICNV compared with controls. However, only IL-17 levels were significantly higher in patients with ICNV compared with controls after adjusting for axial length. Furthermore, there were significant correlations between the levels of IL-10, IL-17, GM-CSF and VEGF and the lesion area. Significant changes in visual acuity and central retinal thickness were observed after IVR. Besides VEGF, IVR also significantly reduced the levels of IL-2, IL-10, basic FGF and IL-12, however, the IL-6 levels were significantly increased. Our results suggest that there may be an involvement of IL-17-related inflammatory processes in the etiology of ICNV.
HMGB1, a pathogenic molecule that induces neurite degeneration via TLR4-MARCKS, is a potential therapeutic target for Alzheimer’s disease
Authors: Fujita Kyota , Motoki Kazumi , Tagawa Kazuhiko , Chen Xigui , Hama Hiroshi , Nakajima Kazuyuki , Homma Hidenori , Tamura Takuya , Watanabe Hirohisa , Katsuno Masahisa , Matsumi Chiemi , Kajikawa Masunori , Saito Takashi , Saido Takaomi , Sobue Gen , Miyawaki Atsushi , Okazawa Hitoshi 
Published: August 2016

AbstractAlzheimer’s disease (AD) is the most common neurodegenerative disease, but it remains an intractable condition. Its pathogenesis is predominantly attributed to the aggregation and transmission of two molecules, Aβ and tau; however, other pathological mechanisms are possible. Here, we reveal that phosphorylation of MARCKS, a submembrane protein that regulates the stability of the actin network, occurs at Ser46 prior to aggregation of Aβ and is sustained throughout the course of AD in human and mouse brains. Furthermore, HMGB1 released from necrotic or hyperexcitatory neurons binds to TLR4, triggers the specific phosphorylation of MARCKS via MAP kinases and induces neurite degeneration, the classical hallmark of AD pathology. Subcutaneous injection of a newly developed monoclonal antibody against HMGB1 strongly inhibits neurite degeneration even in the presence of Aβ plaques and completely recovers cognitive impairment in a mouse model. HMGB1 and Aβ mutually affect polymerization of the other molecule and the therapeutic effects of the anti-HMGB1 monoclonal antibody are mediated by Aβ-dependent and Aβ-independent mechanisms. We propose that HMGB1 is a critical pathogenic molecule promoting AD pathology in parallel with Aβ and tau and a new key molecular target of preclinical antibody therapy to delay the onset of AD.
Gain-loss asymmetry in neural correlates of temporal discounting: An approach-avoidance motivation perspective
Authors: Zhang Yang-Yang , Xu Lijuan , Rao Li-Lin , Zhou Lei , Zhou Yuan , Jiang Tianzi , Li Shu , Liang Zhu-Yuan 
Published: August 2016

AbstractGain-loss asymmetry in temporal discounting (i.e., when individuals discount gains more than losses) has been implicated in numerous problematic and addictive behaviors, resulting in enormous personal and societal costs. On the basis of findings from a previous study, we speculated that approach-avoidance motivation would modulate gain-loss asymmetry. To test this speculation, we examined the effects of motivation on gain-loss asymmetry by analyzing functional connectivity. We found that approach and avoidance motivation were negatively associated with functional connectivity between the medial orbitofrontal cortex (MOFC) and the dorsolateral prefrontal cortex and functional connectivity between the MOFC and the posterior parietal cortex (PPC) in the gain domain. Only avoidance motivation was found to be positively associated with functional connectivity between the medial prefrontal cortex (MPFC) and the posterior cingulate cortex (PCC) as well as between the MPFC and the insula in the loss domain. Our findings suggest that the relationships of approach-avoidance motivation and neural correlates yielded an asymmetrical pattern between the gain and loss domains in temporal discounting. Thus, we provide new insight into understanding gain-loss asymmetry in temporal discounting.
Energy metabolism in intestinal epithelial cells during maturation along the crypt-villus axis
Authors: Yang Huansheng , Wang Xiaocheng , Xiong Xia , Yin Yulong 
Published: August 2016

AbstractIntestinal epithelial cells continuously migrate and mature along crypt-villus axis (CVA), while the changes in energy metabolism during maturation are unclear in neonates. The present study was conducted to test the hypothesis that the energy metabolism in intestinal epithelial cells would be changed during maturation along CVA in neonates. Eight 21-day-old suckling piglets were used. Intestinal epithelial cells were isolated sequentially along CVA, and proteomics was used to analyze the changes in proteins expression in epithelial cells along CVA. The identified differentially expressed proteins were mainly involved in cellular process, metabolic process, biological regulation, pigmentation, multicellular organizational process and so on. The energy metabolism in intestinal epithelial cells of piglets was increased from the bottom of crypt to the top of villi. Moreover, the expression of proteins related to the metabolism of glucose, most of amino acids, and fatty acids was increased in intestinal epithelial cells during maturation along CVA, while the expression of proteins related to glutamine metabolism was decreased from crypt to villus tip. The expression of proteins involved in citrate cycle was also increased intestinal epithelial cells during maturation along CVA. Moreover, dietary supplementation with different energy sources had different effects on intestinal structure of weaned piglets.
Yu Ping Feng San reverses cisplatin-induced multi-drug resistance in lung cancer cells via regulating drug transporters and p62/TRAF6 signalling
Authors: Lou Jian-Shu , Yan Lu , Bi Cathy W. C. , Chan Gallant K. L. , Wu Qi-Yun , Liu Yun-Le , Huang Yun , Yao Ping , Du Crystal Y. Q. , Dong Tina T. X. , Tsim Karl W. K. 
Published: August 2016

AbstractYu Ping Feng San (YPFS), an ancient Chinese herbal decoction composed of Astragali Radix, Atractylodis Macrocephalae Rhizoma and Saposhnikoviae Radix, has been used in the clinic for treating immune deficiency. In cancer therapy, YPFS is being combined with chemotherapy drugs to achieve improved efficacy; however, scientific evidence to illustrate this combination effect is lacking. The present study aims to demonstrate the anti-drug resistance of YPFS in cisplatin (DDP)-resistant non-small cell lung cancer cells (A549/DDP). The application of YPFS exhibited a synergistic enhancement of DDP-induced cytotoxicity as well as of the apoptotic signalling molecules. DDP-induced expression of the multi-drug-resistance efflux transporters was markedly reduced in the presence of YPFS, resulting in a higher intracellular concentration of DDP. In addition, the application of YPFS increased DDP-induced ROS accumulation and MMP depletion, decreased p62/TRAF6 signalling in DDP-treated A549/DDP cells. The co-treatment of DDP and YPFS in tumour-bearing mice reduced the tumour size robustly (by more than 80%), which was much better than the effect of DDP alone. These results indicate that YPFS can notably improve the DDP-suppressed cancer effect, which may be a consequence of the elevation of intracellular DDP via the drug transporters as well as the down regulation of p62/TRAF6 signalling.