bluuebunny/crossref_metadata_2025_split huggingface dataset:
The biosynthetic origin of psychoactive kavalactones in kava
Authors: Pluskal Tomáš , Torrens-Spence Michael P. , Fallon Timothy R. , De Abreu Andrea , Shi Cindy H. , Weng Jing-Ke 
Published: April 2018

AbstractFor millennia, humans have used plants for medicinal purposes. However, our limited understanding of plant biochemistry hinders the translation of such ancient wisdom into modern pharmaceuticals1. Kava (Piper methysticum) is a medicinal plant native to the Polynesian islands with anxiolytic and analgesic properties supported by over 3,000 years of traditional use as well as numerous recent clinical trials2–5. The main psychoactive principles of kava, kavalactones, are a unique class of polyketide natural products known to interact with central nervous system through mechanisms distinct from those of the prescription psychiatric drugs benzodiazepines and opioids6,7. Here we reportde novoelucidation of the biosynthetic pathway of kavalactones, consisting of seven specialized metabolic enzymes. Based on phylogenetic and crystallographic analyses, we highlight the emergence of two paralogous styrylpyrone synthases, both of which have neofunctionalized from an ancestral chalcone synthase to catalyze the formation of the kavalactone scaffold. Structurally diverse kavalactones are then biosynthesized by subsequent regio- and stereo-specific tailoring enzymes. We demonstrate the feasibility of engineering heterologous production of kavalactones and their derivatives in bacterial, yeast, and plant hosts, thus opening an avenue towards the development of new psychiatric therapeutics for anxiety disorders, which affect over 260 million people globally8.
A scalable estimator of SNP heritability for Biobank-scale data
Authors: Wu Yue , Sankararaman Sriram 
Published: April 2018

AbstractMotivationHeritability, the proportion of variation in a trait that can be explained by genetic variation, is an important parameter in efforts to understand the genetic architecture of complex phenotypes as well as in the design and interpretation of genome-wide association studies. Attempts to understand the heritability of complex phenotypes attributable to genome-wide SNP variation data has motivated the analysis of large datasets as well as the development of sophisticated tools to estimate heritability in these datasets.Linear Mixed Models (LMMs) have emerged as a key tool for heritability estimation where the parameters of the LMMs, i.e., the variance components, are related to the heritability attributable to the SNPs analyzed. Likelihood-based inference in LMMs, however, poses serious computational burdens.ResultsWe propose a scalable randomized algorithm for estimating variance components in LMMs. Our method is based on a MoM estimator that has a runtime complexityfor N individuals andMSNPs (whereBis a parameter that controls the number of random matrix-vector multiplications). Further, by leveraging the structure of the genotype matrix, we can reduce the time complexity to.We demonstrate the scalability and accuracy of our method on simulated as well as on empirical data. On standard hardware, our method computes heritability on a dataset of 500, 000 individuals and 100, 000 SNPs in 38 minutes.AvailabilityThe RHE-reg software is made freely available to the research community at:https://github.com/sriramlab/RHE-regContactsriram@cs.ucla.edu
Functional repair after ischemic injury through high efficiency in situ astrocyte-to-neuron conversion
Authors: Chen Yuchen , Ma Ningxin , Pei Zifei , Wu Zheng , Do-Monte Fabricio H. , Huang Pengqian , Yellin Emma , Chen Miranda , Yin Jiuchao , Lee Grace , Minier-Toribio Angélica , Hu Yi , Bai Yuting , Lee Kathryn , Quirk Gregory J. , Chen Gong 
Published: April 2018

ABSTRACTMammalian brains have largely lost internal neural regeneration capability except for a few discrete neurogenic niches. After brain injury, the cerebral cortex is especially difficult to repair due to its extremely low rate of adult neurogenesis. Previous studies have converted glial cells into neurons, but the total number of neurons generated is rather limited, casting doubt about its therapeutic potential. Here, we demonstrate that high-efficiency neuroregeneration can be achieved in adult mammalian brains by making use of an engineered AAV Cre-FLEX system to convert a large number of reactive astrocytes into functional neurons. Specifically, using a combination of GFAP::Cre and FLEX-NeuroD1 AAV system, we were able to regenerate enough new neurons from astrocytes to cover about 40% of the neurons lost from an ischemic injury (400 NeuN+ new neurons/mm2), compared to previously reported an average of <1% of cortical neurons (2-8 NeuN+ neurons/mm2) in an ischemic-injured adult mammalian cortex. Importantly, this in situ astrocyte-to-neuron conversion process also improved survival of injured pre-existing neurons, (additional 400 neurons/mm2), leading to a repaired motor cortex with layered cortical structures. Moreover, NeuroD1-converted neurons not only form functional neural circuits but also rescue motor and memory deficits after ischemic injury. Our results establish the proof-of-principle that a highly efficient in situ astrocyte-to-neuron conversion approach provides a novel treatment for neurological disorders that are in need of new neurons.
Prion protein quantification in cerebrospinal fluid as a tool for prion disease drug development
Authors: Vallabh Sonia M , Nobuhara Chloe K , Llorens Franc , Zerr Inga , Parchi Piero , Capellari Sabina , Kuhn Eric , Klickstein Jacob , Safar Jiri , Nery Flavia , Swoboda Kathryn , Schreiber Stuart L , Geschwind Michael D , Zetterberg Henrik , Arnold Steven E , Minikel Eric Vallabh 
Published: April 2018

AbstractReduction of native prion protein (PrP) levels in the brain is an attractive and genetically validated strategy for the treatment or prevention of human prion diseases. However, clinical development of any PrP-reducing therapeutic will require an appropriate pharmacodynamic biomarker: a practical and robust method for quantifying PrP, and reliably demonstrating its reduction, in the central nervous system (CNS) of a living patient. Here we evaluate the potential of enzyme-linked immunosorbent assay (ELISA)-based quantification of human PrP in human cerebrospinal fluid (CSF) to serve as a biomarker for PrP-reducing therapeutics. We show that CSF PrP is highly sensitive to plastic adsorption during handling and storage, but its loss can be minimized by addition of detergent. We find that blood contamination does not affect CSF PrP levels, and that CSF PrP and hemoglobin are uncorrelated, together suggesting that CSF PrP is CNS-derived, supporting its relevance for monitoring the tissue of interest and in keeping with high PrP abundance in brain relative to blood. In a cohort with controlled sample handling, CSF PrP exhibits good within-subject test-retest reliability (mean coefficient of variation 13% in samples collected 8-11 weeks apart), a sufficiently stable baseline to allow therapeutically meaningful reductions in brain PrP to be readily detected in CSF. Together, these findings supply a method for monitoring the effect of a PrP-reducing drug in the CNS, enabling the development of prion disease therapeutics with this mechanism of action.
Conflict perception: a new scale with evidence from Israel and Palestine
Authors: Khatib Ibrahim , Canetti Daphna , Rubin Aviad 
Published: April 2018

PurposeThe current work aims to introduce the concept of conflict perception and construct a scale that measures individual differences in perceptions about conflicts along religious, national and material dimensions. The concept and the measure are developed in the context of the Israeli–Palestinian conflict.Design/methodology/approachThe research design combines three methodological elements: 14 focus groups in Israel and the West Bank, which represent diversity in place of residence, religion, age and political background; an expert panel review; and a survey of 411 student respondents that was conducted between September 29 and October 9, 2013, among university students in Israel and Palestine.FindingsThe findings show that conflict perception is an individual’s subjective view regarding the essence of the conflict and its central issues, the identities of the parties involved and their motivations, which may include material, ideological or symbolic motives, or any combination thereof. A novel scale consisting of five statements that can measure conflict perception that was developed, validated and implemented via a survey sample showed that Palestinians in the West Bank and in Israel have a religious perception of the conflict, whereas Jews have a national perception of the conflict.Originality/valueFirst, the paper introduces a new concept that sheds additional light on the micro foundations of peoples’ attitudes in conflict situations. Second, it develops and validates a measurement tool for conflict perception that may be usable, with necessary adjustments, in other conflicts. Third, it demonstrates that parties to the conflict do not necessarily share similar perceptions about the conflict, a finding with far-reaching consequences for conflict resolution at both the scholarly and policy levels.
Activation of voltage‐gated sodium current and inhibition of erg‐mediated potassium current caused by telmisartan, an antagonist of angiotensin II type‐1 receptor, in HL‐1 atrial cardiomyocytes
Authors: Chang Wei‐Ting , Wu Sheng‐Nan 
Published: April 2018

SummaryTelmisartan (TEL) is a non‐peptide blocker of angiotensin II type‐1 (AT1) receptor. However, the mechanisms through which this drug interacts directly with ion currents in hearts remain largely unclear. Herein, we aim to investigate the effects of TEL the on ionic currents and membrane potential of murine HL‐1 cardiomyocytes. In whole‐cell recordings, addition of TEL stimulated the peak and late components of voltage‐gated Na+ currents (INa) with different potencies. The EC50 values required to achieve the stimulatory effect of this drug on peak and late INa were 0.2 and 1.2 μmol/L, respectively, and the current‐voltage relationship of peak INa shifted toward less‐depolarized potentials during exposure to TEL. Telmisartan not only increased peak INa but also prolonged the inactivation time course of late INa. Amiodarone (Amio) or ranolazine (Ran), but not angiotensin II, could reverse TEL‐mediated effects. The drug enhanced the recovery rate of INa inactivation and exerted an inhibitory effect on erg‐mediated K+ and L‐type Ca2+ currents. In whole‐cell current‐clamp recordings, addition of the drug resulted in prolongation of the duration of action potentials (APs) in a dose‐dependent manner in HL‐1 cells; Amio or Ran could reverse this increase in AP durations. Telmisartan‐mediated prolongation of AP was attenuated in KCNH2 siRNA‐transfected HL‐1 cells. In cultured smooth muscle cells of the human coronary artery, TEL enhanced INa amplitudes and slowed current inactivation. Stimulation by TEL of INa in HL‐1 cells did not simply increase current magnitude but altered current kinetics, thereby suggesting state‐dependent activation. Telmisartan may have greater affinity to the open/inactivated state than to the resting state residing in NaV channels. Collectively, TEL‐mediated stimulation of INa and inhibition of IK(erg) could be an important ionic mechanism underlying the increased cell excitability of HL‐1 cells; these actions, however, cannot be entirely explained by its blockade of AT1 receptor.
Transient antagonism of anti‐CD20 monoclonal antibodies and PI3K inhibitor idelalisib in DLBCL cell lines
Authors: Zoellner Anna‐Katharina , Peter Nico , Zimmermann Yvonne , Hutter Grit , Hiddemann Wolfgang , Dreyling Martin 
Published: April 2018

AbstractIntroductionPI3K inhibitors are evaluated for relapsed and refractory Diffuse large B‐cell lymphoma (DLBCL) patients.ObjectiveAs rituximab has shown to influence B‐cell receptor (BCR) signaling, we investigated the interaction of anti‐CD20 antibody rituximab and the new type II glycoengineered anti‐CD20 antibody obinutuzumab in combination with the PI3K delta inhibitor idelalisib.MethodsEstablished DLBCL cell lines were treated with either rituximab or obinutuzumab alone or in combination with PI3K delta inhibitor idelalisib.ResultsRituximab and to a lesser extent obinutuzumab monotherapy resulted in a temporary upregulation of p‐Akt, p42/44, and p38 signaling pathways.Idelalisib reduced p‐Akt expression. Rituximab antagonized the p‐Akt downregulation at early time points, while obinutuzumab did not interfere with idelalisib's effects. In cell growth analysis, early antagonism could also be detected.ConclusionThe combination of idelalisib with CD antibodies shows an initial antagonism of rituximab but not obinutuzumab in downregulation of PI3K‐signaling targets.
A novel type of +2‐base pair frameshift CALR mutation in a patient with myeloproliferative neoplasm
Authors: Kim Hyun‐Young , Kim Jong‐Won , Kim Sun‐Hee , Chang Myung Hee , Kim Hee‐Jin 
Published: April 2018

AbstractSomatic CALR mutations have been identified in the majority of JAK2 mutation‐negative essential thrombocythaemia (ET) and primary myelofibrosis. Almost all CALR mutations have been reported to typically generate a +1‐base pair (bp) frameshift in the open reading frame. Here, we describe an ET patient with a +2‐bp frameshift CALR mutation. A 41‐year‐old man was admitted because of headache, and diagnosed as JAK2‐negative ET. After 4 years, his disease progressed to post‐ET myelofibrosis, and CALR mutation analysis demonstrated a +2‐bp frameshift CALR mutation caused by two different CALR mutations, c.1139_1151del and c.1211_1215delinsTTGA, on the same allele. The resultant mutant protein sequence shared 19 amino acids with those from type 1 and type 2 CALR mutations, but the downstream C‐terminal sequences were different. To our knowledge, CALR double mutations causing +2‐bp frameshift are extremely rare. Identification of this novel type of CALR mutation has potential implications for better understanding of CALR oncogenesis.
Prospective real‐world analysis of OnabotulinumtoxinA in chronic migraine post‐National Institute for Health and Care Excellence UK technology appraisal
Authors: Andreou A. P. , Trimboli M. , Al‐Kaisy A. , Murphy M. , Palmisani S. , Fenech C. , Smith T. , Lambru G. 
Published: April 2018

Background and purposeThe National Institute for Health and Care Excellence (NICE) in the UK recommends the use of OnabotulinumtoxinA (BoNTA, Botox®) in the management of chronic migraine (CM) following specific guidelines within the National Health Service. In view of the lack of data on the efficacy of this therapy following implementation of these guidelines in clinical practice and on the evaluation of guidance compliance, we aimed to evaluate the effectiveness and safety of BoNTA in patients with CM following the NICE guidelines.MethodsThis was a prospective real‐life audit study.ResultsAfter two treatments, 127 of 200 patients (63.5%) obtained at least a 30% reduction in headache days. Those who continued the treatment up to 3 years reported a stable beneficial effect compared with baseline. Amongst responders, 68 patients (53.5%) were reclassified as episodic migraineurs. A total of 57 of these patients (83.8%) converted to an episodic migraine pattern at 6‐month follow‐up. The majority of those whose migraine became episodic after BoNTA extended the treatment intervals beyond 3 months (range 4–8 months) before noticing any worsening of headache. We observed no significant differences in the efficacy measures in patients treated with 155 U BoNTA compared with those treated with >155 U BoNTA.ConclusionsWhen administered according to the NICE guidance, BoNTA produced a clinically meaningful effect in the long‐term management of CM with and without medication overuse headache. Treatment discontinuation when CM becomes episodic may be useful in clinical practice to identify those who may benefit from extended treatment intervals. Our clinical experience indicates a lack of additional benefit from using the ‘follow‐the‐pain’ paradigm.
PCSK9 plays a novel immunological role in oxidized LDL‐induced dendritic cell maturation and activation of T cells from human blood and atherosclerotic plaque
Authors: Liu A. , Frostegård J. 
Published: April 2018

AbstractBackgroundActivated T cells and dendritic cells (DCs) occur in atherosclerotic plaques. Proprotein convertase subtilisin kexin 9 (PCSK9) targets the LDL‐receptor (LDLR) and results in increased LDL levels. We here investigate immune effects of PCSK9 on OxLDL induced DC maturation and T‐cell activation.MethodsT cells were isolated from carotid specimens of patients undergoing carotid endarterectomy or from peripheral blood of healthy individuals. Human peripheral blood monocytes were differentiated into DCs. Naïve T cells were cocultured with pretreated DCs. The effects of PCSK9 and its inhibition by silencing were studied.ResultsOxLDL induced PCSK9 in DCs and promoted DC maturation with increased expressions of CD80, CD83, CD86 and HLA‐DR and the scavenger receptors LOX‐1 and CD36. T cells exposed to OxLDL‐treated DCs proliferated and produced IFN‐γ and IL‐17, thus with polarization to Th1 and/or Th17 subsets. Silencing of PCSK9 reversed the OxLDL effects on DCs and T cells. DC maturation was repressed, and the production of TNF‐α, IL‐1β and IL‐6 was limited, while TGF‐β and IL‐10 secretion and T regulatory cells were induced. OxLDL induced miRNA let‐7c, miR‐27a, miR‐27b, miR‐185. Silencing PCSK9 repressed miR‐27a and to a lesser extent let‐7c. PCSK9 silencing enhanced SOCS1 expression induced by OxLDL. Experiments on T cells from carotid atherosclerotic plaques or healthy individuals showed similar results.ConclusionsWe demonstrate immunological effects of PCSK9 in relation to activation and maturation of DCs and plaque T cells by OxLDL, a central player in atherosclerosis. This may directly influence atherosclerosis and cardiovascular disease, independent of LDL lowering.
Collections‐based science in the 21st Century
Authors: Funk Vicki A. 
Published: April 2018

AbstractDiscoveries from collections‐based science change the way we perceive ourselves, our environment, and our place in the universe. The 18thCentury saw the beginning of formal classification with Linnaeus proposing a system to classify all of life. The 19thCentury ushered in the age of exploration as naturalists undertook large‐scale collecting expeditions leading to major scientific advances (the founding of Physical Geography, Meteorology, Ecology, Biogeography, and Evolution) and challenging long held beliefs about nature. In the 20thCentury collections were central to paradigm shifts, including theories of Continental Drift and Phylogenetic Systematics; Molecular Phylogenetics added testable hypotheses, and computerized specimen records gave rise to the field of Biodiversity. In the first 15 years of the 21stCentury we have seen tree‐thinking pervade the life sciences, leading to the emergence of Evolutionary Medicine, Evolutionary Ecology, and new Food Safety methods. More advances are on the way: (i) Open access to large amounts of specimen data & images, (ii) Linking of collections and climate data to phylogenies on a global scale, and (iii) Production of vast quantities of genomic data allowing us to address big evolutionary questions. As a result of collections‐based science people see themselves not as the center of all things but rather as part of a complex universe. It is essential that we integrate new discoveries with knowledge from the past (e.g., collections) in order to understand this planet we all inhabit. To ensure the health of collections‐based science we must come together and plan for the future.
Internet addiction and attention‐deficit–hyperactivity disorder: Effects of anxiety, depression and self‐esteem
Authors: Kahraman Özlem , Demirci Esra Özdemir 
Published: April 2018

AbstractBackgroundAttention‐deficit–hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood. Behavioral disinhibition, poor neurocognitive skills and immediate reward preference in children with ADHD have been suggested as risk factors for Internet addiction (IA). The aim of the present study was therefore to investigate the relationship between IA and depression, anxiety, and self‐esteem in adolescents with ADHD, and to identify the features of Internet use that predict IA.MethodsWe studied 111 patients with ADHD aged 12–18 years, and 108 healthy controls. The ADHD patients and controls were asked to complete a sociodemographic data form, the Internet Addiction Scale (IAS), Children's Depression Inventory, Childhood Screening Scale for Anxiety in Children, and the Rosenberg Self‐Esteem Scale.ResultsIAS total score in the adolescents with ADHD was significantly higher than in the control group. Compared with the control group, the ADHD group depression scale score was significantly higher, and self‐esteem score significantly lower (P < 0.05 for both). There was no difference between the groups in anxiety score. IAS score had a positive correlation with depression and anxiety scores, and a negative correlation with self‐esteem score.ConclusionThe relationship between IA scale score and depression, anxiety and self‐esteem scale scores were similar in the ADHD and the control group. In addition, IAS subscale and total scores were significantly higher in the ADHD group than the control group, even after controlling for the effects of self‐esteem, depression and anxiety scores. Thus, ADHD is thought to be an independent risk factor for depression, anxiety and self‐esteem, and, hence, for IA.
Réformes électorales et changements institutionnels dans un contexte de démocratisation. Le choix du scrutin uninominal sous la Troisième République en France
Authors: Ehrhard Thomas , Passard Cédric 
Published: April 2018

RésuméL'article étudie le choix du mode de scrutin uninominal sous la Troisième République à partir de l'analyse des débats parlementaires des trois lois électorales qui installent ou rétablissent ce mode de scrutin (1875, 1889 et 1927). Il interroge les intérêts électoraux des acteurs politiques avec les enjeux de la démocratisation et de l’évolution du régime politique.Il montre que les réformes électorales sont utilisées stratégiquement pour tenter de limiter l'irruption de nouveaux acteurs politiques et pour rendre plus difficile la mise en cause de l’équilibre institutionnel. En profitant aux acteurs républicains notabilisés, le mode de scrutin uninominal, pourtant d'abord perçu comme un héritage des régimes autoritaires, favorise l'installation durable de la République. La démocratisation apparaît au final comme un processus qui ne s'appuie pas seulement sur des objectifs démocratiques.