bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Na+/H+ Exchanger Nhe1 Modulates Network Excitability via GABA Release
Authors: Bocker Hartmut T , Heinrich Theresa , Liebmann Lutz , Hennings J Christopher , Seemann Eric , Gerth Melanie , Jakovčevski Igor , Preobraschenski Julia , Kessels Michael M , Westermann Martin , Isbrandt Dirk , Jahn Reinhard , Qualmann Britta , Hübner Christian A 
Published: November 2018

Abstract
Brain functions are extremely sensitive to pH changes because of the pH-dependence of proteins involved in neuronal excitability and synaptic transmission. Here, we show that the Na+/H+ exchanger Nhe1, which uses the Na+ gradient to extrude H+, is expressed at both inhibitory and excitatory presynapses. We disrupted Nhe1 specifically in mice either in Emx1-positive glutamatergic neurons or in parvalbumin-positive cells, mainly GABAergic interneurons. While Nhe1 disruption in excitatory neurons had no effect on overall network excitability, mice with disruption of Nhe1 in parvalbumin-positive neurons displayed epileptic activity. From our electrophysiological analyses in the CA1 of the hippocampus, we conclude that the disruption in parvalbumin-positive neurons impairs the release of GABA-loaded vesicles, but increases the size of GABA quanta. The latter is most likely an indirect pH-dependent effect, as Nhe1 was not expressed in purified synaptic vesicles itself. Conclusively, our data provide first evidence that Nhe1 affects network excitability via modulation of inhibitory interneurons.
No Singular Modulus Is a Unit
Authors: Bilu Yuri , Habegger Philipp , Kühne Lars 
Published: November 2018

Abstract
A result of the 2nd-named author states that there are only finitely many complex multiplication (CM)-elliptic curves over $\mathbb{C}$ whose $j$-invariant is an algebraic unit. His proof depends on Duke’s equidistribution theorem and is hence noneffective. In this article, we give a completely effective proof of this result. To be precise, we show that every singular modulus that is an algebraic unit is associated with a CM-elliptic curve whose endomorphism ring has discriminant less than $10^{15}$. Through further refinements and computer-assisted arguments, we eventually rule out all remaining cases, showing that no singular modulus is an algebraic unit. This allows us to exhibit classes of subvarieties in ${\mathbb{C}}^n$ not containing any special points.
Algebraic Tangent Cones of Reflexive Sheaves
Authors: Chen Xuemiao , Sun Song 
Published: November 2018

Abstract
We study the notion of algebraic tangent cones at singularities of reflexive sheaves. These correspond to extensions of reflexive sheaves across a negative divisor. We show the existence of optimal extensions in a constructive manner, and we prove the uniqueness in a suitable sense. The results here are an algebro-geometric counterpart of our previous study on singularities of Hermitian–Yang–Mills connections.
High Constitutive Interleukin 10 Level Interferes With the Immune Response to Varicella-Zoster Virus in Elderly Recipients of Live Attenuated Zoster Vaccine
Authors: Gershon Anne A , Brooks David , Stevenson Donald D , Chin William K , Oldstone Michael B A , Gershon Michael D 
Published: November 2018

AbstractIntroductionLive attenuated zoster vaccine (Zostavax) was used to test the hypothesis that constitutive level of interleukin 10 (IL-10), which may be high in elderly subjects, impairs vaccine efficacy. If constitutive IL-10 impairs vaccine efficacy, the effectiveness of viral vaccines might be improved by transient inhibition of IL-10 before vaccination.MethodsZostavax was given to 26 patients (age, 60–80 years). IL-10 and immunity to varicella zoster virus (VZV) were measured at baseline and after vaccination. Fluorescent antibody to membrane antigen (FAMA) assays and glycoprotein enzyme-linked immunosorbent assays (gpELISAs) were used to assess humoral immunity; anti–varicella virus T-cell responses were studied in a subset of subjects. In a prospective animal model, T-cell responses to chimeric vaccines against lymphocytic choriomeningitis virus (LCMV) were assessed in mice that express or lack IL-10.ResultsFAMA assays revealed significant boosting (by 4-fold) of humoral immunity, which occurred only in subjects (10 of 26) with a low constitutive IL-10 level (ie, <20 pg/mL); moreover, the Zostavax-induced FAMA and gpELISA responses were inversely related to the constitutive IL-10 level. Significant VZV-specific T-cell responses followed vaccination only in subjects with a low constitutive IL-10 level. Vaccine-induced LCMV-specific T-cell responses in mice lacking IL-10 were greater than in wild-type animals.ConclusionsA high constitutive IL-10 level adversely affects vaccine efficacy.
‘Responsibility’, change, and rising powers’ role conceptions: comparing Indian foreign policy roles in global climate change negotiations and maritime security
Authors: Plagemann Johannes , Prys-Hansen Miriam 
Published: November 2018

Abstract
Strong economic growth and assertive political leadership have made India an increasingly prominent player in global governance. Whereas conventional scholarship of India’s foreign policy underlines continuity, this article explores how India’s self-conception has changed across two policy fields (climate change and maritime security). Adopting a role-theoretical approach, we analyze official statements as a mirror of both India’s self-understanding and its view on the roles of significant other actors. Although both issue-areas exhibit change, India’s self-ascribed role has been transformed more profoundly in the maritime domain. Our comparison suggests three factors to particularly induce transformation of rising powers’ roles toward ‘more responsibility’: First, power-sharing is more conducive than burden-sharing; second, issue-areas with strong regional anchors are more likely to induce the adoption of a more responsible role than those areas situated primarily at the global level of politics; and third, positive external role ascriptions are more effective than negative ones.
Automated and flexible identification of complex disease: building a model for systemic lupus erythematosus using noisy labeling
Authors: Murray Sara G , Avati Anand , Schmajuk Gabriela , Yazdany Jinoos 
Published: November 2018

Abstract

Accurate and efficient identification of complex chronic conditions in the electronic health record (EHR) is an important but challenging task that has historically relied on tedious clinician review and oversimplification of the disease. Here we adapt methods that allow for automated “noisy labeling” of positive and negative controls to create a “silver standard” for machine learning to automate identification of systemic lupus erythematosus (SLE). Our final model, which includes both structured data as well as text processing of clinical notes, outperformed all existing algorithms for SLE (AUC 0.97). In addition, we demonstrate how the probabilistic outputs of this model can be adapted to various clinical needs, selecting high thresholds when specificity is the priority and lower thresholds when a more inclusive patient population is desired. Deploying a similar methodology to other complex diseases has the potential to dramatically simplify the landscape of population identification in the EHR.

MeSH terms
Electronic Health Records, Machine Learning, Lupus Erythematosus, Phenotype, Algorithms
Pregnancy-Associated Plasma Protein-A (PAPP-A) in Ewing Sarcoma: Role in Tumor Growth and Immune Evasion
Authors: Heitzeneder Sabine , Sotillo Elena , Shern Jack F , Sindiri Sivasish , Xu Peng , Jones Robert , Pollak Michael , Noer Pernille R , Lorette Julie , Fazli Ladan , Alag Anya , Meltzer Paul , Lau Ching , Conover Cheryl A , Oxvig Claus , Sorensen Poul H , Maris John M , Khan Javed , Mackall Crystal L 
Published: November 2018

AbstractBackgroundEwing sarcoma (EWS) manifests one of the lowest somatic mutation rates of any cancer, leading to a scarcity of druggable mutations and neoantigens. Immunotherapeutics targeting differentially expressed cell surface antigens could provide therapeutic benefit for such tumors. Pregnancy-associated plasma protein A (PAPP-A) is a cell membrane-associated proteinase produced by the placenta that promotes fetal growth by inducing insulinlike growth factor (IGF) signaling.MethodsBy comparing RNA expression of cell surface proteins in EWS (n = 120) versus normal tissues (n = 42), we comprehensively characterized the surfaceome of EWS to identify highly differentially expressed molecules. Using CRISPR/Cas-9 and anti-PAPP-A antibodies, we investigated biological roles for PAPP-A in EWS in vitro and in vivo in NSG xenograft models and performed RNA-sequencing on PAPPA knockout clones (n = 5) and controls (n = 3). All statistical tests were two-sided.ResultsEWS surfaceome analysis identified 11 highly differentially overexpressed genes, with PAPPA ranking second in differential expression. In EWS cell lines, genetic knockout of PAPPA and treatment with anti-PAPP-A antibodies revealed an essential survival role by regulating local IGF-1 bioavailability. MAb-mediated PAPPA inhibition diminished EWS growth in orthotopic xenografts (leg area mm2 at day 49 IgG2a control (CTRL) [n = 14], mean = 397.0, SD = 86.1 vs anti-PAPP-A [n = 14], mean = 311.7, SD = 155.0; P = .03; median OS anti-PAPP-A = 52.5 days, 95% CI = 46.0 to 63.0 days vs IgG2a = 45.0 days, 95% CI = 42.0 to 52.0 days; P = .02) and improved the efficacy of anti-IGF-1R treatment (leg area mm2 at day 49 anti-PAPP-A + anti-IGF-1R [n = 15], mean = 217.9, SD = 148.5 vs IgG2a-CTRL; P < .001; median OS anti-PAPP-A + anti-IGF1R = 63.0 days, 95% CI = 52.0 to 67.0 days vs IgG2a-CTRL; P < .001). Unexpectedly, PAPPA knockout in EWS cell lines induced interferon (IFN)-response genes, including proteins associated with antigen processing/presentation. Consistently, gene expression profiles in PAPPA-low EWS tumors were enriched for immune response pathways.ConclusionThis work provides a comprehensive characterization of the surfaceome of EWS, credentials PAPP-A as a highly differentially expressed therapeutic target, and discovers a novel link between IGF-1 signaling and immune evasion in cancer, thus implicating shared mechanisms of immune evasion between EWS and the placenta.
Pediatric Office Delivery of Smoking Cessation Assistance for Breast-Feeding Mothers
Authors: Drehmer Jeremy E , Ossip Deborah J , Nabi-Burza Emara , Hipple Walters Bethany , Gorzkowski Julie A , Winickoff Jonathan P 
Published: November 2018

Abstract

Introduction
National and international organizations have done an excellent job of advocating and promoting breast feeding for all mothers. This study assessed to what extent an intervention increased delivery of cessation assistance to breast-feeding mothers who smoke.

Methods
Data were collected between April and October 2015 in five US states as part of a cluster randomized controlled trial in 10 pediatric practices. Practices were randomized to the Clinical Effort Against Secondhand Smoke Exposure (CEASE) intervention or usual care control arms. Mothers were asked about their smoking status and breast-feeding history during a screening interview upon exiting the practice and eligible mothers who agreed to participate in an enrollment interview were asked if they received smoking cessation assistance during their child’s visit. Mothers with a child 1 year old and younger were included in the analyses.

Results
Current breast feeding was associated with a reduced likelihood of current smoking (adjusted odds ratio [aOR] = 0.38, 95% confidence interval [95% CI] = 0.25 to 0.57) and a greater likelihood of quitting smoking (aOR = 2.33, 95% CI = 1.29 to 4.21) after controlling for known confounders. Mothers who concurrently smoked and breast-fed were more likely to be asked about smoking (66.7% vs. 28.6%, p = .01), advised to quit (61.1% vs. 21.4%, p &lt; .01), prescribed nicotine replacement therapy (50.0% vs. 0%, p &lt; .001), and enrolled into the quitline (27.8% vs. 0%, p &lt; .01) at CEASE practices compared to control practices.

Conclusion
Breast-feeding mothers were less likely to be current smokers and more likely to have recently quit smoking. Among mothers who continue to smoke and breast feed, the CEASE intervention enhances delivery of smoking cessation assistance.

Implications
Breast feeding and eliminating infants’ exposure to tobacco smoke are important protective factors for serious pediatric health risks including sudden infant death. This study shows that breast feeding was positively associated with desirable tobacco control outcomes, specifically that breast feeding was associated with a lower likelihood of smoking among ever smokers and a greater likelihood of recently quitting smoking. This is also the first study to look specifically at delivery of smoking cessation assistance to breast-feeding mothers seen at pediatric offices and demonstrates the effectiveness of delivering evidence-based smoking cessation assistance to them in this context.

Trial Registration
www.ClinicalTrials.gov (identifier NCT01882348).
Secular trends in the incidence and prevalence of gout in Denmark from 1995 to 2015: a nationwide register-based study
Authors: Zobbe Kristian , Prieto-Alhambra Daniel , Cordtz René , Højgaard Pil , Hindrup Jens Skøt , Kristensen Lars Erik , Dreyer Lene 
Published: November 2018

Abstract

Objective
To investigate temporal trends in the incidence and prevalence of gout in the adult Danish population.

Methods
Using the nationwide Danish National Patient Registry, we calculated the number of incident gout patients (per 100 000 person-years) within each 1 year period from 1995 to 2015 and the prevalence of gout in 2000 and 2015. Further, we calculated age- and gender-specific incidence rates of gout from 1995 to 2015.

Results
We identified a total of 45 685 incident gout patients (72.9% males) with a mean age of 65 years (s.d. 16) at diagnosis. In both genders, an increase in age-standardized incidence rates was observed from 32.3/100 000 (95% CI 30.7, 33.9) in 1995 to 57.5/100 000 (95% CI 55.6, 59.5) in 2015 (P < 0.001). Similar trends were observed for 8950 cases diagnosed in rheumatology departments. We likewise observed an increase in the prevalence of gout from 0.29% (95% CI 0.29, 0.30) in 2000 to 0.68% (95% CI 0.68, 0.69) in 2015.

Conclusions
The annual incidence rate of gout increased by almost 80% in Denmark between 1995 and 2015. The prevalence increased by nearly 130% between 2000 and 2015. Reasons for this are unknown but may include an increase in risk factors (e.g. obesity, diabetes mellitus), longer life expectancy and increased awareness of the disease among patients and/or health professionals.
External Validity and Policy Adaptation: From Impact Evaluation to Policy Design
Authors: Williams Martin J 
Published: November 2018

AbstractWith the growing number of impact evaluations worldwide, the question of how to apply this evidence in policy making processes has arguably become the main challenge for evidence-based policy making. How can policy makers predict whether a policy will have the same impact in their context as it did elsewhere, and how should this influence the policy’s design and implementation? This paper suggests that failures of external validity (both in transporting and scaling up policy) can be understood as arising from an interaction between a policy’s theory of change and a dimension of the context in which it is being implemented. The paper surveys existing approaches to analyzing external validity, and suggests that there has been more focus on the generalizability of impact evaluation results than on the applicability of evidence to specific contexts. To help fill this gap, the study develops a method of “mechanism mapping” that maps a policy’s theory of change against salient contextual assumptions to identify external validity problems and suggest appropriate policy adaptations. In deciding whether and how to adapt a policy, there is a fundamental informational trade-off between the strength of evidence on the policy from other contexts and the policy maker’s information about the local context.
Complete heart block in systemic sclerosis
Authors: Wang Qinghai , Shang Yinghui , Li Shicheng , Wu Yanxiang , Wang Chenyu , Yan Xiaowei 
Published: November 2018

Abstract

Rationale:
Complete heart block (CHB) is a common clinical manifestation. Systemic sclerosis (SSc) is a rare etiology of CHB that has not received enough attention. Whether pacemaker implantation is required remains inconclusive, especially when patients have no symptoms or mild symptoms of CHB.

Patient concerns:
In this study, we report the case of a 48-year-old Chinese male who suffers from SSc and CHB.

Diagnose:
The patient was previously diagnosed with left anterior hemiblock (LAHB) and right bundle block with normal heart function. CHB was observed on a regular follow-up electrocardiogram (ECG) examination 1 month before his hospitalization.

Interventions:
A permanent dual chamber pacemaker was implanted.

Outcomes:
The patient responded well to pacemaker implantation treatment, and his exertional dyspnea disappeared.

Lessons:
The occurrence of heart block associated with SSc often appears concealed. The case highlights the importance of regular follow-up of a patient with SSc. Pacemaker implantation might be unavoidable if CHB is secondary to SSc, even if it is asymptomatic.
Modified quadruple therapy versus bismuth-containing quadruple therapy in first-line treatment of Helicobacter pylori infection in Korea; rationale and design of an open-label, multicenter, randomized controlled trial
Authors: Lim Hyun , Bang Chang Seok , Shin Woon Geon , Choi Jae Ho , Soh Jae Seung , Kang Ho Suk , Yang Young Joo , Hong Ji Taek , Shin Suk Pyo , Suk Ki Tae , Lee Jae Jun , Baik Gwang Ho , Kim Dong Joon 
Published: November 2018

Abstract

Background:
Clarithromycin-containing triple regimen for eradication of Helicobacter pylori is no longer acceptable in Korea due to high clarithromycin resistance. Concomitant therapy or bismuth-containing quadruple therapy is recommended as an alternative regimen. A recent study in Korea has shown that modified quadruple therapy has comparable efficacy and safety to concomitant therapy as a first-line regimen. However, there has been no comparative study of modified quadruple therapy with bismuth-containing quadruple therapy. The aim of this study is to compare the efficacy and safety of modified quadruple therapy with those of bismuth-containing quadruple therapy as a first-line regimen and to present the phenotypic and genotypic antibiotic resistance profile of H pylori.

Methods:
This study is an open-label, multicenter, randomized controlled trial. We are recruiting subjects endoscopically diagnosed with H pylori infection from 2 hospitals in Korea. Subjects will be randomly allocated either to modified quadruple therapy (proton-pump inhibitor bid, amoxicillin 1 g bid, metronidazole 500 mg tid, bismuth subcitrate 300 mg qid daily) or bismuth-containing quadruple therapy (proton-pump inhibitor bid, tetracycline 500 mg qid, metronidazole 500 mg tid, bismuth subcitrate 300 mg qid daily) for 14 days. The rate of eradication success and adverse events will be checked at least 4 weeks after the treatment. Antibiotic resistance will be established using both a bacterial culture with agar dilutions and DNA sequencing of the clarithromycin resistance point mutations in the 23S rRNA gene of H pylori.

Conclusion:
The results of this study will provide solid evidence for determining the optimal treatment regimen for first-line H pylori eradication in Korea.
Psychiatric risk geneNT5C2regulates protein translation in human neural progenitor cells
Authors: Duarte Rodrigo R.R. , Bachtel Nathaniel D. , Côtel Marie-Caroline , Lee Sang H. , Selvackadunco Sashika , Watson Iain A. , Hovsepian Gary A. , Troakes Claire , Breen Gerome D. , Nixon Douglas F. , Murray Robin M. , Bray Nicholas J. , Eleftherianos Ioannis , Vernon Anthony C. , Powell Timothy R. , Srivastava Deepak P. 
Published: November 2018

AbstractGenome-wide significant variants associated with combined risk for major psychiatric disorders on chromosome 10q24 affect the expression of the cytosolic 5’-nucleotidase II (NT5C2, cN-II) in population controls, implicating it as a psychiatric susceptibility gene. Risk alleles are associated with reduced expression of this gene in the developing and adult brain, but the resulting neurobiological risk mechanisms remain elusive. In this study, we provide further evidence for the association ofNT5C2with psychiatric disorders, and use a functional genetics approach to gain a deeper understanding of the function of this risk gene in the nervous system.NT5C2expression was significantly reduced in thepost-mortembrain of schizophrenia and bipolar disorder patients, and its protein predominately expressed in neurons within the adult brain. Using human neural progenitor cells (hNPCs), we found thatNT5C2expression peaked at the neural progenitor state, where the encoded protein was ubiquitously distributed through the cell.NT5C2knockdown in hNPCs elicited transcriptomic changes associated with protein translation, that were accompanied by regulation of adenosine monophosphate-activated protein kinase (AMPK) signalling and ribosomal protein S6 (rpS6) activity. To identify the effect of reduced neuronalNT5C2expression at a systems level, we knockdown its homologue,CG32549, inDrosophila melanogasterCNS. This elicited impaired climbing behaviour in the model organism. Collectively, our data implicateNT5C2expression in risk for psychiatric disorders and inDrosophila melanogastermotility, and further suggest that risk is mediated via regulation of AMPK signalling and protein translation during early neurodevelopment.
Ensembles from ordered and disordered proteins reveal similar structural constraints during evolution
Authors: Marchetti Julia , Monzon Alexander Miguel , Tosatto Silvio C.E. , Parisi Gustavo , Fornasari María Silvina 
Published: November 2018

AbstractInter-residue contacts determine the structural properties for each conformer in the ensembles describing the native state of proteins. Structural constraints during evolution could then provide biologically relevant information about the conformational ensembles and their relationship with protein function. Here, we studied the proportion of sites evolving under structural constraints in two very different types of ensembles, those coming from ordered or disordered proteins. Using a structurally constrained model of protein evolution we found that both types of ensembles show comparable, near 40%, number of positions evolving under structural constraints. Among these sites, ~68% are in disordered regions and ~57% of them show long-range inter-residue contacts. Also, we found that disordered ensembles are redundant in reference to their structurally constrained evolutionary information and could be described on average with ~11 conformers. Despite the different complexity of the studied ensembles and proteins, the similar constraints reveal a comparable level of selective pressure to maintain their biological functions. These results highlight the importance of the evolutionary information to recover meaningful biological information to further characterize conformational ensembles.