bluuebunny/crossref_metadata_2025_split huggingface dataset:
Common variants at 2q11.2, 8q21.3, and 11q13.2 are associated with major mood disorders
Authors: Xiao Xiao , Wang Lu , Wang Chuang , Yuan Ti-Fei , Zhou Dongsheng , Zheng Fanfan , Li Lingyi , Grigoroiu-Serbanescu Maria , Ikeda Masashi , Iwata Nakao , Takahashi Atsushi , Kamatani Yoichiro , Kubo Michiaki , Preisig Martin , Kutalik Zoltán , Castelao Enrique , Pistis Giorgio , Amin Najaf , van Duijn Cornelia M. , Forstner Andreas J. , Strohmaier Jana , Hecker Julian , Schulze Thomas G. , Müller-Myhsok Bertram , Reif Andreas , Mitchell Philip B. , Martin Nicholas G. , Schofield Peter R. , Cichon Sven , Nöthen Markus M. , Chang Hong , Luo Xiong-Jian , Fang Yiru , Yao Yong-Gang , Zhang Chen , Rietschel Marcella , Li Ming ,   Advanced Collaborative Study of Mood Disorder (COSMO) Team, MooDS Bipolar Consortium
Published: December 2017

AbstractBipolar disorder (BPD) and major depressive disorder (MDD) are primary major mood disorders. Recent studies suggest that they share certain psychopathological features and common risk genes, but unraveling the full genetic architecture underlying the risk of major mood disorders remains an important scientific task. The public genome-wide association study (GWAS) data sets offer the opportunity to examine this topic by utilizing large amounts of combined genetic data, which should ultimately allow a better understanding of the onset and development of these illnesses. Genome-wide meta-analysis was performed by combining two GWAS data sets on BPD and MDD (19,637 cases and 18,083 controls), followed by replication analyses for the loci of interest in independent 12,364 cases and 76,633 controls from additional samples that were not included in the two GWAS data sets. The single-nucleotide polymorphism (SNP) rs10791889 at 11q13.2 was significant in both discovery and replication samples. When combining all samples, this SNP and multiple other SNPs at 2q11.2 (rs717454), 8q21.3 (rs10103191), and 11q13.2 (rs2167457) exhibited genome-wide significant association with major mood disorders. The SNPs in 2q11.2 and 8q21.3 were novel risk SNPs that were not previously reported, and SNPs at 11q13.2 were in high LD with potential BPD risk SNPs implicated in a previous GWAS. The genome-wide significant loci at 2q11.2 and 11q13.2 exhibited strong effects on the mRNA expression of certain nearby genes in cerebellum. In conclusion, we have identified several novel loci associated with major mood disorders, adding further support for shared genetic risk between BPD and MDD. Our study highlights the necessity and importance of mining public data sets to explore risk genes for complex diseases such as mood disorders.
A general pharmacodynamic interaction model identifies perpetrators and victims in drug interactions
Authors: Wicha Sebastian G. , Chen Chunli , Clewe Oskar , Simonsson Ulrika S. H. 
Published: December 2017

AbstractAssessment of pharmacodynamic (PD) drug interactions is a cornerstone of the development of combination drug therapies. To guide this venture, we derive a general pharmacodynamic interaction (GPDI) model for ≥2 interacting drugs that is compatible with common additivity criteria. We propose a PD interaction to be quantifiable as multidirectional shifts in drug efficacy or potency and explicate the drugs’ role as victim, perpetrator or even both at the same time. We evaluate the GPDI model against conventional approaches in a data set of 200 combination experiments in Saccharomyces cerevisiae: 22% interact additively, a minority of the interactions (11%) are bidirectional antagonistic or synergistic, whereas the majority (67%) are monodirectional, i.e., asymmetric with distinct perpetrators and victims, which is not classifiable by conventional methods. The GPDI model excellently reflects the observed interaction data, and hence represents an attractive approach for quantitative assessment of novel combination therapies along the drug development process.
Ezh2 phosphorylation state determines its capacity to maintain CD8+ T memory precursors for antitumor immunity
Authors: He Shan , Liu Yongnian , Meng Lijun , Sun Hongxing , Wang Ying , Ji Yun , Purushe Janaki , Chen Pan , Li Changhong , Madzo Jozef , Issa Jean-Pierre , Soboloff Jonathan , Reshef Ran , Moore Bethany , Gattinoni Luca , Zhang Yi 
Published: December 2017

AbstractMemory T cells sustain effector T-cell production while self-renewing in reaction to persistent antigen; yet, excessive expansion reduces memory potential and impairs antitumor immunity. Epigenetic mechanisms are thought to be important for balancing effector and memory differentiation; however, the epigenetic regulator(s) underpinning this process remains unknown. Herein, we show that the histone methyltransferase Ezh2 controls CD8+ T memory precursor formation and antitumor activity. Ezh2 activates Id3 while silencing Id2, Prdm1 and Eomes, promoting the expansion of memory precursor cells and their differentiation into functional memory cells. Akt activation phosphorylates Ezh2 and decreases its control of these transcriptional programs, causing enhanced effector differentiation at the expense of T memory precursors. Engineering T cells with an Akt-insensitive Ezh2 mutant markedly improves their memory potential and capability of controlling tumor growth compared to transiently inhibiting Akt. These findings establish Akt-mediated phosphorylation of Ezh2 as a critical target to potentiate antitumor immunotherapeutic strategies.
IL-33 is induced in undifferentiated, non-dividing esophageal epithelial cells in eosinophilic esophagitis
Authors: Travers J. , Rochman M. , Caldwell J. M. , Besse J. A. , Miracle C. E. , Rothenberg M. E. 
Published: December 2017

AbstractThe molecular and cellular etiology of eosinophilic esophagitis (EoE), an emerging tissue-specific allergic disease, involves dysregulated gene expression in esophageal epithelial cells. Herein, we assessed the esophageal expression of IL-33, an epithelium-derived alarmin cytokine, in patients with EoE. IL-33 protein was markedly overexpressed within the nuclei of a subpopulation of basal layer esophageal epithelial cells in patients with active EoE compared to control individuals. IL-33 exhibited dynamic expression as levels normalized upon EoE remission. IL-33–positive basal epithelial cells expressed E-cadherin and the undifferentiated epithelial cell markers keratin 5 and 14 but not the differentiation marker keratin 4. Moreover, the IL-33–positive epithelial cells expressed the epithelial progenitor markers p75 and p63 and lacked the proliferation markers Ki67 and phospho-histone H3. Additionally, the IL-33–positive cells had low expression of PCNA. IL-33 expression was detected in ex vivo–cultured primary esophageal epithelial cells in a subpopulation of cells lacking expression of proliferation markers. Collectively, we report that IL-33 expression is induced in an undifferentiated, non-dividing esophageal epithelial cell population in patients with active EoE.
SHP2 associates with nuclear localization of STAT3: significance in progression and prognosis of colorectal cancer
Authors: Huang Yan , Wang Jie , Cao Fuao , Jiang Hailong , Li An , Li Jianzhong , Qiu Lei , Shen Hao , Chang Wenjun , Zhou Chuanxiang , Pan Yamin , Lu Yiming 
Published: December 2017

AbstractTyrosine phosphatase SHP2, encoded by PTPN11, has been implicated in many physiologic and pathologic processes in neoplastic progression. However, controversies are emerging from many studies, indicating SHP2 has a dual role in different types of tumors. We aimed to explore the role of SHP2 in progression and prognosis of colorectal cancer (CRC). SHP2 inhibited CRC cell proliferation and migration, and the phosphorylation of STAT3 was negatively regulated by SHP2 in CRC. SHP2 and nuclear STAT3 were examined in 270 CRC tissues. SHP2 was significantly correlated with nuclear STAT3 (Spearman’s rho = −0.408, P ≤ 0.001). Based on Cox regression analysis, patients with high levels of SHP2 and low levels of nuclear STAT3 had longer disease-specific survival (DSS) (HR, 0.362; 95% CI, 0.165–0.794) and disease-free survival (DFS) (HR, 0.447; 95% CI, 0.227–0.877). Further, low levels of SHP2 and high levels of nuclear STAT3 were independently associated with adverse outcomes in the whole cohort (DFS; HR, 2.353; 95% CI, 1.199–4.619). These results suggest that combination of SHP2 and nuclear STAT3 is a strong prognostic predictor in CRC.
Parallelogram based approach for in vivo dose estimation of genotoxic metabolites in humans with relevance to reduction of animal experiments
Authors: Motwani Hitesh V. , Frostne Cecilia , Törnqvist Margareta 
Published: December 2017

AbstractWhen employing metabolism studies of genotoxic compounds/metabolites and cancer tests for risk estimation, low exposure doses in humans are roughly extrapolated from high exposure doses in animals. An improvement is to measure the in vivo dose, i.e. area under concentration-time curve (AUC), of the causative genotoxic agent. In the present work, we propose and evaluate a parallelogram based approach for estimation of the AUC of genotoxic metabolites that incorporates in vitro metabolic data and existing knowledge from published in vivo data on hemoglobin (Hb) adduct levels, using glycidamide (GA) as a case study compound that is the genotoxic metabolite of acrylamide (AA). The estimated value of AUC of GA per AUC of AA from the parallelogram approach vs. that from Hb adduct levels measured in vivo were in good agreement; 0.087 vs. 0.23 in human and 1.4 vs. 0.53 in rat, respectively. The described parallelogram approach is simple, and can be useful to provide an approximate estimation of the AUC of metabolites in humans at low exposure levels for which sensitive methods for analyzing the metabolites are not available, as well as aid in reduction of animal experiments for metabolism studies that are to be used for cancer risk assessment.
Immune microenvironment of experimental rat C6 gliomas resembles human glioblastomas
Authors: Gieryng Anna , Pszczolkowska Dominika , Bocian Katarzyna , Dabrowski Michal , Rajan Wenson David , Kloss Michal , Mieczkowski Jakub , Kaminska Bozena 
Published: December 2017

AbstractGlioblastoma (GBM) is the most aggressive primary brain tumor, with ineffective anti-tumor responses and a poor prognosis despite aggressive treatments. GBM immune microenvironment is heterogenous and activation of specific immune populations in GBM is not fully characterized. Reliable animal models are critical for defining mechanisms of anti-tumor immunity. First we analyzed the immune subpopulations present in rat C6 gliomas. Using flow cytometry we determined kinetics of infiltration of myeloid cells and T lymphocytes into glioma-bearing brains. We found significant increases of the amoeboid, pro-tumorigenic microglia/macrophages, T helper (Th) and T regulatory (Treg) cells in tumor-bearing brains, and rare infiltrating T cytotoxic (Tc) cells. Transcriptomic analyses of glioma-bearing hemispheres revealed overexpression of invasion and immunosuppression-related genes, reflecting the immunosuppressive microenvironment. Microglia, sorted as CD11b+CD45low cells from gliomas, displayed the pro-invasive and immunosuppressive type of activation. Accumulation of Th and Treg cells combined with the reduced presence of Tc lymphocytes in rat gliomas may result in the lack of effective anti–tumor responses. Transcriptional profiles of CD11b+ cells and composition of immune infiltrates in C6 gliomas indicate that rat C6 gliomas employ similar immune system evasion strategies as human GBMs.
The celecoxib derivatives AR-12 and AR-14 induce autophagy and clear prion-infected cells from prions
Authors: Abdulrahman Basant A. , Abdelaziz Dalia , Thapa Simrika , Lu Li , Jain Shubha , Gilch Sabine , Proniuk Stefan , Zukiwski Alexander , Schatzl Hermann M. 
Published: December 2017

AbstractPrion diseases are fatal infectious neurodegenerative disorders that affect both humans and animals. The autocatalytic conversion of the cellular prion protein (PrPC) into the pathologic isoform PrPSc is a key feature in prion pathogenesis. AR-12 is an IND-approved derivative of celecoxib that demonstrated preclinical activity against several microbial diseases. Recently, AR-12 has been shown to facilitate clearance of misfolded proteins. The latter proposes AR-12 to be a potential therapeutic agent for neurodegenerative disorders. In this study, we investigated the role of AR-12 and its derivatives in controlling prion infection. We tested AR-12 in prion infected neuronal and non-neuronal cell lines. Immunoblotting and confocal microscopy results showed that AR-12 and its analogue AR-14 reduced PrPSc levels after only 72 hours of treatment. Furthermore, infected cells were cured of PrPSc after exposure of AR-12 or AR-14 for only two weeks. We partially attribute the influence of the AR compounds on prion propagation to autophagy stimulation, in line with our previous findings that drug-induced stimulation of autophagy has anti-prion effects in vitro and in vivo. Taken together, this study demonstrates that AR-12 and the AR-14 analogue are potential new therapeutic agents for prion diseases and possibly protein misfolding disorders involving prion-like mechanisms.
Fractal analysis of collision cascades in pulsed-ion-beam-irradiated solids
Authors: Wallace J. B. , Aji L. B. Bayu , Shao L. , Kucheyev S. O. 
Published: December 2017

AbstractThe buildup of radiation damage in ion-irradiated crystals often depends on the spatial distribution of atomic displacements within collision cascades. Although collision cascades have previously been described as fractals, the correlation of their fractal parameters with experimental observations of radiation damage buildup remains elusive. Here, we use a pulsed-ion-beam method to study defect interaction dynamics in 3C-SiC irradiated at 100 °C with ions of different masses. These data, together with results of previous studies of SiC and Si, are analyzed with a model of radiation damage formation which accounts for the fractal nature of collision cascades. Our emphasis is on the extraction of the effective defect diffusion length from pulsed beam measurements. Results show that, for both Si and SiC, collision cascades are mass fractals with fractal dimensions in the range of ~1–2, depending on ion mass, energy, and the depth from the sample surface. Within our fractal model, the effective defect diffusion length is ~10 nm for SiC and ~20 nm for Si, and it decreases with increasing cascade density. These results demonstrate a general method by which the fractal nature of collision cascades can be used to explain experimental observations and predict material’s response to radiation.
Hybrid splicing minigene and antisense oligonucleotides as efficient tools to determine functional protein/RNA interactions
Authors: Cywoniuk Piotr , Taylor Katarzyna , Sznajder Łukasz J. , Sobczak Krzysztof 
Published: December 2017

AbstractAlternative splicing is a complex process that provides a high diversity of proteins from a limited number of protein-coding genes. It is governed by multiple regulatory factors, including RNA-binding proteins (RBPs), that bind to specific RNA sequences embedded in a specific structure. The ability to predict RNA-binding regions recognized by RBPs using whole-transcriptome approaches can deliver a multitude of data, including false-positive hits. Therefore, validation of the global results is indispensable. Here, we report the development of an efficient and rapid approach based on a modular hybrid minigene combined with antisense oligonucleotides to enable verification of functional RBP-binding sites within intronic and exonic sequences of regulated pre-mRNA. This approach also provides valuable information regarding the regulatory properties of pre-mRNA, including the RNA secondary structure context. We also show that the developed approach can be used to effectively identify or better characterize the inhibitory properties of potential therapeutic agents for myotonic dystrophy, which is caused by sequestration of specific RBPs, known as muscleblind-like proteins, by mutated RNA with expanded CUG repeats.
Ecosystem respiration and its components in a rainfed spring maize cropland in the Loess Plateau, China
Authors: Gao Xiang , Mei Xurong , Gu Fengxue , Hao Weiping , Li Haoru , Gong Daozhi 
Published: December 2017

AbstractWe estimated ecosystem respiration (Re) and its components in a rainfed spring maize field in the Loess Plateau, China, during the growing seasons of 2012, 2013, and 2014 using measurements of eddy covariance and soil respiration (Rs). The multi-factor equation, which included photosynthetic active radiation, 5-cm soil temperature, 10-cm soil water content, and green leaf area index (GLAI), had goodness-of-fit values of between 0.81 and 0.94 for Re, autotrophic respiration (Ra), and above-ground autotrophic respiration (Raa), and goodness-of-fit values of between 0.50 and 0.67 for Rs, below-ground autotrophic respiration (Rab), and heterotrophic respiration (Rh). The highly significant linear correlations between gross primary production (GPP) and Re and its components indicate that GPP had a strong influence on Re and its components. The growing season Re was dominated by Ra (64–71%), which in turn was dominated by Raa (63–73%). Although Rs was mainly made up of Rh (56–61%), Rs resembled Rab more closely than Rh. The relationships between GLAI and Ra/Re and between GLAI and Rab/Rs were described by logarithmic equations with goodness-of-fit values of between 0.88 and 0.89 and between 0.77 and 0.84, respectively, indicating that GLAI controlled Ra/Re and Rab/Rs.
Anti-corrosion performance of the synergistic properties of benzenecarbonitrile and 5-bromovanillin on 1018 carbon steel in HCl environment
Authors: Loto Roland Tolulope 
Published: December 2017

AbstractThe synergistic properties of the combined admixture of benzenecarbonitrile and 5-bromovanillin (BNV) on the corrosion resistance of 1018 carbon steel in 1 M HCl was analysed with potentiodynamic polarization technique, weight loss method, micro-analytical studies and ATF-FTIR spectroscopy. Results obtained show the admixed organic compound was effective with optimal corrosion inhibition values of 99.33% and 90.34% at 1.25% BNV concentration from both electrochemical methods due to the effective inhibition action and passivation characteristics of the protonated inhibitor molecules in the acid solution. Primary amines, stretch alkyl halides and C-H triple bond functional groups of the molecules were observed to actively adsorb during the corrosion inhibition reaction from ATF-FTIR spectroscopic analysis. Calculations from thermodynamic evaluation confirmed cationic adsorption mechanism to be chemisorption obeying the Langmuir and Frumkin adsorption isotherm. Micro-analytical observations of the inhibited carbon steel morphology significantly contrast the unprotected steel due to visible surface deterioration and presence of micro/macro-pits. The organic derivatives showed mixed type inhibition reactions.
The Listening and Spoken Language Data Repository: Design and Project Overview
Authors: Bradham Tamala S. , Fonnesbeck Christopher , Toll Alice , Hecht Barbara F. 
Published: December 2017

Purpose
The purpose of the Listening and Spoken Language Data Repository (LSL-DR) was to address a critical need for a systemwide outcome data–monitoring program for the development of listening and spoken language skills in highly specialized educational programs for children with hearing loss highlighted in Goal 3b of the 2007 Joint Committee on Infant Hearing position statement supplement.

Method
The LSL-DR is a multicenter, international data repository for recording and tracking the demographics and longitudinal outcomes achieved by children who have hearing loss who are enrolled in private, specialized programs focused on supporting listening and spoken language development. Since 2010, annual speech-language-hearing outcomes have been prospectively obtained by qualified clinicians and teachers across 48 programs in 4 countries.

Results
The LSL-DR has been successfully implemented, bringing together the data collection efforts of these programs to create a large and diverse data repository of 5,748 children with hearing loss.

Conclusion
Due to the size and diversity of the population, the range of assessments entered, and the demographic information collected, the LSL-DR will provide an unparalleled opportunity to examine the factors that influence the development of listening in spoken language in this population.
Use of Non–Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation Patients with Malignancy: Clinical Practice Experience in a Single Institution and Literature Review
Authors: Rago Anna , Papa Andrea , Meo Federica , Attena Emilio , Golino Paolo , D'Onofrio Antonio , Nigro Gerardo , Russo Vincenzo 
Published: December 2017

AbstractThis observational study aimed to investigate the efficacy and safety of non–vitamin K antagonist oral anticoagulants (NOACs) in atrial fibrillation (AF) patients with malignancy. A total of 76 patients (mean age: 73.2 ± 8.9; 28 females) with AF and malignancy treated with NOAC were included in the analysis. The mean CHA2DS2-VASc and HAS-BLED scores were 3.2 ± 1.2 and 2.2 ± 0.9, respectively. The study population was taking dabigatran 150 mg (25%) twice daily (BID), apixaban 5 mg BID (25%), dabigatran 110 mg BID (24%), rivaroxaban 20 mg (18%) once a day (OD), rivaroxaban 15 mg OD (5%), or apixaban 2.5 mg OD (3%). NOAC therapy began, on average, 248 ± 238 days before malignancy diagnosis for an average duration of 1,000 ± 289 days. Stroke, transient ischemic attack, major and minor bleeding events, other adverse effects, and major cardiovascular complications during the follow-up period were collected. In our study population, no patients experienced thromboembolic events during therapy with any NOAC. We recorded a low global incidence of major bleeding (3.9%) with a mean annual incidence of 1.4%. No hemorrhagic stroke or subarachnoid hemorrhage was observed. Only nine patients (11.8%) experienced minor bleeding. According to our data, anticoagulation therapy with NOACs seems to be an effective and safe treatment strategy for nonvalvular AF patients with malignancy.