bluuebunny/crossref_metadata_2025 huggingface dataset:
Reassessing Carbamazepine in the Treatment of Bipolar Disorder Clinical Implications of New Data
Authors: Ketter Terence A. , Ginsberg David L. , Akiskal Hagop S. , Keck Paul E. , Weisler Richard H. , Hirschfeld Robert M.A. , Hollander Eric
Published: May 2019

This monograph summarizes the proceedings of a roundtable meeting convened to discuss the role of carbamazepine in the treatment of bipolar disorder, in light of new data and the recent indication of carbamazepine extended-release capsules (CBZ ERC) for use in the treatment of acute manic and mixed episodes. Two lectures were presented, followed by a panel discussion among all 6 participants. A summary of the two pivotal trials of CBZ ERC and their pooled data along with other relevant data is presented first. Next, historical trends of carbamazepine and the agent's use in acute mania, bipolar depression, and maintenance are reviewed, emphasizing clinical implications of efficacy, safety, tolerability, and drug interactions. Finally, the panel discussion provides recommendations for the use of carbamazepine in different phases of the illness, taking into account adverse effects and drug-drug interactions.

Panel discussants agree that current data confirm the utility of CBZ ERC as an effective treatment for acute manic and mixed episodes in bipolar disorder. Carbamazepine may also prove to be an option for maintenance treatment. Tolerability of the drug is related to dose and titration, and overall safety limitations regarding carbamazepine usage are comparable to other medications. For some patients, the main challenges to use of carbamazepine may be common drug-drug interactions and increased side effects related to aggressive introduction during treatment of acute manic and mixed episodes. Thus, carbamazepine may be a lower priority option for patients who are taking multiple medications, such as elderly individuals with medical comorbidity, due to the potential for drug interactions. Important benefits of carbamazepine include the low propensity toward weight gain and evidence of good tolerability with long-term treatment. (At present there are no available data from long-term, placebo-controlled studies evaluating the effects of carbamazepine or CBZ ERC on weight.) Thus, carbamazepine may be a good option for patients who are concerned about weight gain or who are intolerant of or respond poorly to other medications. Further efforts are needed to update physicians on the use of carbamazepine relative to other medications in the treatment of bipolar disorder.
Studies of Carbamazepine Extended-Release Capsules in Bipolar Disorder
Authors: Weisler Richard H.
Published: May 2019

This discussion reviews data from two 3-week, double-blind, placebo-controlled pivotal trials of carbamazepine extended release capsules (CBZ ERC; SPD417.301 and SPD417.304); pooled results from these trials; data from a 3-week, double-blind, placebo-controlled trial in lithium non-responders or non-tolerators (SPD417.302); and additional supportive data from a 6-month, open-label, extension trial (SPD417.303). In addition, information on a retrospective chart review of 600 adolescent and adult bipolar patients on CBZ ERC is presented.

In the first large double-blind, placebo-controlled study assessing CBZ ERC in acute mania, manic and mixed bipolar patients from multiple centers were hospitalized and all medications were discontinued. After reaching a stable baseline 2–5 days later, the patients were randomized to CBZ ERC (n=101; 59% with mixed states) or placebo (n=103; 47% with mixed states) for 3 weeks. An aggressive initial titration schedule was implemented, beginning with 200 mg BID and increased by 200 mg/day until good clinical response was achieved or the patient could not tolerate the dosage. Many patients were taking 1,200–1,600 mg/day by the end of week 1. Efficacy was assessed using the Young Mania Rating Scale (YMRS). The Clinical Global Impressions (CGI) scale and the Hamilton Rating Scale for Depression (HAM-D) were also followed.
Understanding Early Childhood Resilience Following Neonatal Brain Injury From Parents’ Perspectives Using a Mixed-Method Design
Authors: Williams Tricia S. , McDonald Kyla P. , Roberts Samantha D. , Westmacott Robyn , Dlamini Nomazulu , Tam Emily W.Y.
Published: May 2019

Objectives:The current study used a mixed-method design to qualitatively examine parents’ definitions of resilience and factors they believed optimized their child’s early outcome following neonatal brain injury. This was followed by quantitative analyses of early developmental and mental health outcomes and their relation to salient biopsychosocial factors.Methods:Participants were parents of children diagnosed with neonatal brain injury due to stroke or hypoxic-ischemic encephalopathy (N=51; age range of children 18 months to 8 years). The Parent Experiences Questionnaire (PEQ) was used to qualitatively analyze parents’ open-ended responses about their child’s early experiences and outcome. The Child Behavior Checklist (CBCL) and Scales of Independent Behaviour Early Developmental Form (SIB-ED) parent ratings were used to measure child resilience from a quantitative perspective, identifying “at-risk” and “resilient” children using standard cutoffs. “Resilient” and “at-risk” children were compared on biopsychosocial variables using univariatettests and chi-square analyses.Results:Parents provided five unique definitions of their child’s positive outcomes, and many children demonstrated resilience based on parent perspectives and quantitative definitions. Supporting factors included close medical follow-up, early intervention, and intrinsic factors within the child and parent. Group comparisons of “resilient” and “at-risk” children highlighted the importance of parent mental health across these early developmental and mental health outcomes.Conclusions:Many children were described as resilient during the early years by parents using qualitative and quantitative approaches. Findings highlighted the importance of parent well-being in promoting optimal early outcomes. (JINS, 2019,25, 390–402.)
Automaticity of speech processing in early bilingual adults and children
Authors: Datta Hia , Hestvik Arild , Vidal Nancy , Tessel Carol , Hisagi Miwako , Wróblewski Marcin , Shafer Valerie L.
Published: May 2019

We examine whether early acquisition of a second language (L2) leads to native-like neural processing of phonemic contrasts that are absent in the L1. Four groups (adult and child monolingual speakers of English; adult and child early bilingual speakers of English and Spanish, exposed to both languages before 5 years of age) participated in a study comparing the English /ɪ/ - /ε/ contrast. Neural measures of automatic change detection (Mismatch Negativity, MMN) and attention (Processing Negativity, PN and Late Negativity, LN) were measured by varying whether participants tracked the stimulus stream or not. We observed no effect of bilingualism on the MMN, but adult bilinguals differed significantly from adult monolinguals on neural indices of attention. The child bilinguals were indistinguishable from their monolingual peers. This suggest that learning a L2 before five years of age leads to native-like phoneme discrimination, but bilinguals develop increased attentional sensitivity to speech sounds.
Monte Carlo Simulation on the CD-SEM Images of SiO2/Si Systems
Authors: Zhang P.
Published: May 2019

Silicon dioxide (SiO2) has been the most important insulator in the highly-developed field of silicon (Si) technology. Accurate pitch and gate linewidth measurements for SiO2/Si systems (systems with a SiO2 insulating layer and Si substrate) have become necessary. Studying one such system obviously presents different results from that of the widely researched Si/Si structure, because the edge profile of the secondary electron (SE) signal contains contributions from two materials. In this work, several scanning electron microscope (SEM) images and SE profiles of SiO2/Si pitch and trapezoidal line structures, using various geometric and experimental parameters, were simulated through the use of Monte Carlo (MC) methods. It was found that, in contrast to Si/Si systems, the height of the insulating layer cannot be ignored during the evaluation of pitch and linewidth. The thickness (i.e., height) factor does play an important role in the contrast of SEM imaging and the shape of the SE profile in these two-material systems. The mechanism of the influence of insulating layer thickness for imaging was studied in detail. In addition, the SiO2/Si pitch structure with a real rough surface was also studied. This work has significant implications for the study of various kinds of two-material systems and could help to optimize the pitch and gate linewidth measurements.
Single layer miniaturized ultra-thin FSS with five closely spaced bands
Authors: Dey Anupam , Sanyal Rajarshi
Published: May 2019

This Paper reveals a novel single layer five band frequency selective surface (FSS). Novelties of the proposed FSS lie in its five closely spaced stop bands at 2.4, 3.38, 4.82, 6.32, and 7.75 GHz as well as the reduced single layer structural thickness (0.0016 λ0) and the miniaturized unit cell size (0.0656 λ0) at lower resonant frequency as compared to the existing multiband FSS. The unit cell structure consists of six octagonal concentric interconnected loops. Adjacent loop interconnection technique reduces the cell size by more than 44%. Furthermore, arrow-shaped rings are also introduced on each corner of the outermost octagonal loop, and using this technique approximate 23% cell miniaturization can be achieved. In addition, the proposed FSS exhibits excellent angular stability.
Design and modeling of an ultra-wideband low-noise distributed amplifier in InP DHBT technology
Authors: Shivan T. , Kaule E. , Hossain M. , Doerner R. , Johansen T. , Stoppel D. , Boppel S. , Heinrich W. , Krozer V. , Rudolph M.
Published: May 2019

This paper reports on an ultra-wideband low-noise distributed amplifier (LNDA) in a transferred-substrate InP double heterojunction bipolar transistor (DHBT) technology which exhibits a uniform low-noise characteristic over a large frequency range. To obtain very high bandwidth, a distributed architecture has been chosen with cascode unit gain cells. Each unit cell consists of two cascode-connected transistors with 500 nm emitter length and ft/fmax of ~360/492 GHz, respectively. Due to optimum line-impedance matching, low common-base transistor capacitance, and low collector-current operation, the circuit exhibits a low-noise figure (NF) over a broad frequency range. A 3-dB bandwidth from 40 to 185 GHz is measured, with an NF of 8 dB within the frequency range between 75 and 105 GHz. Moreover, this circuit demonstrates the widest 3-dB bandwidth operation among all reported single-stage amplifiers with a cascode configuration. Additionally, this work has proposed that the noise sources of the InP DHBTs are largely uncorrelated. As a result, a reliable prediction can be done for the NF of ultra-wideband circuits beyond the frequency range of the measurement equipment.
Revising the self-report strengths and difficulties questionnaire for cross-country comparisons of adolescent mental health problems: the SDQ-R
Authors: Duinhof E. L. , Lek K. M. , de Looze M. E. , Cosma A. , Mazur J. , Gobina I. , Wüstner A. , Vollebergh W. A. M. , Stevens G. W. J. M.
Published: May 2019

Aims

The Strengths and Difficulties Questionnaire (SDQ) has been used in many epidemiological studies to assess adolescent mental health problems, but cross-country comparisons of the self-report SDQ are scarce and so far failed to find a good-fitting, common, invariant measurement model across countries. The present study aims to evaluate and establish a version of the self-report SDQ that allows for a valid cross-country comparison of adolescent self-reported mental health problems.

Methods

Using the Health Behaviour in School-aged Children study, the measurement model and measurement invariance of the 20 items of the self-report SDQ measuring adolescent mental health problems were evaluated. Nationally representative samples of 11-, 13- and 15-year old adolescents (n = 33 233) from seven countries of different regions in Europe (Bulgaria, Germany, Greece, the Netherlands, Poland, Romania, Slovenia) were used.

Results

In order to establish a good-fitting and common measurement model, the five reverse worded items of the self-report SDQ had to be removed. Using this revised version of the self-report SDQ, the SDQ-R, partial measurement invariance was established, indicating that latent factor means assessing conduct problems, emotional symptoms, peer relationships problems and hyperactivity-inattention problems could be validly compared across the countries in this study. Results showed that adolescents in Greece scored relatively low on almost all problem subscales, whereas adolescents in Poland scored relatively high on almost all problem subscales. Adolescents in the Netherlands reported the most divergent profile of mental health problems with the lowest levels of conduct problems, low levels of emotional symptoms and peer relationship problems, but the highest levels of hyperactivity-inattention problems.

Conclusions

With six factor loadings being non-invariant, partial measurement invariance was established, indicating that the 15-item SDQ-R could be used in our cross-country comparison of adolescent mental health problems. To move the field of internationally comparative research on adolescent mental health forward, studies should test the applicability of the SDQ-R in other countries in- and outside Europe, continue to develop the SDQ-R as a cross-country invariant measure of adolescent mental health, and examine explanations for the found country differences in adolescent mental health problems.
The History and Afterlife of Soviet Demography: The Socialist Roots of Post-Soviet Neoliberalism
Authors: Leykin Inna
Published: May 2019

The discourse on the demographic crisis in contemporary Russia resonates with a neoliberal political project that attempts to govern populations through the market logic of optimization, responsibilization, and efficacy. Yet, as this article argues, the basic categories of the discourse, although evocative of a new neoliberal rationality, were in fact born of epistemological changes that took place in the Soviet science of population in the last decades of the USSR. Specifically, the analytical shift from Marxist-Leninist demography, which stressed a strong economic determinism, to the concept of demographic behavior, which became central to the discipline's analytical toolkit in the late Soviet period, produced political ideas in which individual behavior became both the core of the population problem and its solution. The article follows these institutional and conceptual transformations and shows how knowledge produced by Soviet demographers in that period continues to provide the foundation for neoliberal state efforts to solve the population problem. When seen from a historical perspective, the neoliberal character of the new population policies loses its apparent ideological and political coherence.
Bringing Oil to Life: Corporations and Conspiracies in Russian Oil Documentaries
Authors: Rogers Douglas
Published: May 2019

This article examines several documentary films made by and about the Russian oil industry in the period from 2003 to 2016, with a particular emphasis on the ways in which they portray intersections between oil and post-Soviet “life.” It divides these films into two major sub-genres: the corporate documentary (2003-present) and the conspiracy documentary (most widespread after about 2012). Corporate documentaries have been instrumental in fashioning new, post-Soviet links between the oil industry and everyday life, especially through “commodity chain” documentaries shown widely on television and in other media. The conspiracy films of the 2010s then extended these commodity chains into the realm of shadowy international cabals and, in some cases, fantastic alien worlds. Together, these sub-genres speak to the cultural imagination of life in Russia as a petrostate, complete with agents and victims, usable pasts and presents, and a variety of energopolitical subject positions that viewers might inhabit and shift among. Although oil documentaries and science fiction generated around the world have long imagined non-hydrocarbon energy futures for humankind, recent Russian oil documentaries in both sub-genres envision a world in which oil and human life will become ever more tightly enmeshed.
Qualitätsmerkmale in der 24 h-Betreuung aus der Perspektive der Betroffenen - Ergebnisse einer Pilotbefragungsstudie in Österreich
Authors: Haslinger-Baumann Elisabeth , Lilgenau Anneliese , Binder Claudia , Gugenberger Katharina
Published: May 2019

Zusammenfassung. Hintergrund: Von den knapp 460 000 Pflegegeldbeziehenden in Österreich werden 80 % zu Hause betreut. Im Jahr 2018 sind über 32 000 Personen zu Hause von insgesamt knapp 65 000 24 h-Personenbetreuer / -innen versorgt worden. Isolierte Arbeitssituationen in Kombination mit komplexen Erkrankungen der Versorgten, einer oft nicht adäquaten Ausbildung und mangelnden Sprachkenntnissen der Personenbetreuer / -innen, wirken sich herausfordernd auf die Versorgungsqualität aus. Fragestellung / Ziel: Ziel der Pilotstudie ist die Beschreibung von Qualitätsmerkmalen in der 24 h-Personenbetreuung aus der Perspektive der beteiligten Akteurinnen und Akteure. Die Forschungsfrage bezieht sich erstens auf die individuell erlebte und zweitens auf die gewünschte Betreuungsqualität. Methoden: Die angewendete Erhebungsmethode ist eine Einzelbefragung entlang eines Leitfadens, als Auswertungsmethode wurde die zusammenfassende Inhaltsanalyse gewählt. Ergebnisse: Insgesamt wurden 32 Interviews (14 Angehörige, ein Klient, acht Personenbetreuer / -innen und neun Diplomierte Gesundheits- und Krankenpflegepersonen) durchgeführt. Im Analyseprozess konnten mittels der entwickelten Hauptkategorie „handlungsfeldorientierte Qualitätsmerkmale“ alle genannten Aspekte abgebildet werden. Diese beziehen sich auf umfassende Alltagsbetreuung / fachpflegerische und medizinische Tätigkeiten, individuelle Betreuung, Sprachkenntnisse und Kommunikation, sowie Aus- und Fortbildung und Schnittstellenmanagement. Schlussfolgerungen: Zur Sicherung einer nachhaltigen Betreuungsqualität ist die Entwicklung von verbindlichen Qualitätskriterien samt kontinuierlicher externer Begleitung essentiell. Dies könnte von den etablierten Sozialverbänden übernommen werden.
Observations of Bedform Migration and Bedload Sediment Transport in Combined Wave‐Current Flows
Authors: Wengrove M. E. , Foster D. L. , Lippmann T. C. , de Schipper M. A. , Calantoni J.
Published: May 2019

Bedload transport is an important mechanism for sediment flux in the nearshore. Yet few studies examine the relationship between bedform evolution and net sediment transport. Our work contributes concurrent observations of bedform mobility and bedload transport in response to wave dominant, current dominant, and combined wave‐current flows in the nearshore. Bedload sediment flux from migrating bedforms during combined wave‐current conditions accounted for at least 20% more bedload transport when compared with wave dominant flows and at least 80% more than current‐dominant flows. Bedforms were observed to transport the most sediment during periods with strong currents, with high‐energy skewed waves, and while bedform orientation and transport direction were aligned. Regardless of flow type, bedform migration rates were directly proportional to the total kinetic energy contained in the flow field. Eleven bedload transport models formulated to be used in combined flows (both shear and energetics based) were compared with sediment flux estimated from measured bedform migration. An energetics based sediment transport model was most representative for our data.
New Constraints on the Origin of the EM‐1 Component Revealed by the Measurement of the La‐Ce Isotope Systematics in Gough Island Lavas
Authors: Boyet M. , Doucelance R. , Israel C. , Bonnand P. , Auclair D. , Suchorski K. , Bosq C.
Published: May 2019

Hot spot lavas show a large diversity of isotope compositions resulting from the recycling of surface material into the convective mantle. Amongst the mantle end‐members, EM‐1 (enriched mantle) is widely debated and scenarios involving either old pelagic sediments subducted into the deep mantle or subcontinental lithospheric material incorporated at shallow depths are commonly evoked. We selected 12 lavas from Gough Island (south Atlantic Ocean) for the measurement of 138La‐138Ce, 147Sm‐143Nd, and 176Lu‐177Hf isotope systems. Results show limited ranges for ε143Nd, ε138Ce, and ε176Hf values, and Ce/Ce* do not correlate with measured isotope ratios. Cerium isotope compositions allow us to exclude the contribution of old sedimentary material carrying a negative, elemental cerium anomaly in the mantle source. Pelagic sediments are indeed characterized by strongly negative, elemental cerium anomalies and also high La/Ce ratios. Modeling a primitive mantle source contaminated by 0.4% to 2.2% of different 2.5 Ga‐old pelagic components is able to reproduce the lowest Ce/Ce* values. However, the cerium isotope measurements show ε138Ce values between −0.39 and 0.15, too low to give support to the incorporation of recycled pelagic sediments in the mantle source of the lavas. Our results suggest that the incorporation of subcontinental lithospheric material at shallow depths during the plume ascent is a more suitable model to explain the formation of the EM‐1 component. Hafnium and Nd isotopes also support this scenario. Subcontinental lithosphere sampled via kimberlites and lamproites has isotopic compositions that plot generally below the mantle array, a signature that is also seen in Gough lavas.
Gross Primary Productivity of Four European Ecosystems Constrained by Joint CO2 and COS Flux Measurements
Authors: Spielmann F. M. , Wohlfahrt G. , Hammerle A. , Kitz F. , Migliavacca M. , Alberti G. , Ibrom A. , El‐Madany T. S. , Gerdel K. , Moreno G. , Kolle O. , Karl T. , Peressotti A. , Delle Vedove G.
Published: May 2019

Gross primary productivity (GPP), the gross uptake of carbon dioxide (CO2) by plant photosynthesis, is the primary driver of the land carbon sink, which presently removes around one quarter of the anthropogenic CO2 emissions each year. GPP, however, cannot be measured directly and the resulting uncertainty undermines our ability to project the magnitude of the future land carbon sink. Carbonyl sulfide (COS) has been proposed as an independent proxy for GPP as it diffuses into leaves in a fashion very similar to CO2, but in contrast to the latter is generally not emitted. Here we use concurrent ecosystem‐scale flux measurements of CO2 and COS at four European biomes for a joint constraint on CO2 flux partitioning. The resulting GPP estimates generally agree with classical approaches relying exclusively on CO2 fluxes but indicate a systematic underestimation under low light conditions, demonstrating the importance of using multiple approaches for constraining present‐day GPP.
Methylamine-specific methyltransferase paralogs in Methanosarcina are functionally distinct despite frequent gene conversion
Authors: Nayak Dipti D , Metcalf William W
Published: May 2019

Sequenced archaeal genomes are mostly smaller and more streamlined than typical bacterial genomes; however, members of the Methanosarcina genus within the Euryarchaeaota are a significant exception, with M. acetivorans being the largest archaeal genome (5.8 Mbp) sequenced thus far. This finding is partially explained by extensive gene duplication within Methanosarcina spp. Significantly, the evolutionary pressures leading to gene duplication and subsequent genome expansion have not been well investigated, especially with respect to biological methane production (methanogenesis), which is the key biological trait of these environmentally important organisms. In this study, we address this question by specifically probing the functional evolution of two methylamine-specific methyltransferase paralogs in members of the Methanosarcina genus. Using the genetically tractable strain, M. acetivorans, we first show that the two paralogs have distinct cellular functions: one being required for methanogenesis from methylamine, the other for use of methylamine as a nitrogen source. Subsequently, through comparative sequence analyses, we show that functional divergence of paralogs is primarily mediated by divergent evolution of the 5′ regulatory region, despite frequent gene conversion within the coding sequence. This unique evolutionary paradigm for functional divergence of genes post-duplication underscores a divergent role for an enzyme singularly associated with methanogenic metabolism in other aspects of cell physiology.
Differential methylation of enhancer at IGF2 is associated with abnormal dopamine synthesis in major psychosis
Authors: Pai Shraddha , Li Peipei , Killinger Bryan , Marshall Lee , Jia Peixin , Liao Ji , Petronis Arturas , Szabó Piroska E. , Labrie Viviane
Published: May 2019

Impaired neuronal processes, including dopamine imbalance, are central to the pathogenesis of major psychosis, but the molecular origins are unclear. Here we perform a multi-omics study of neurons isolated from the prefrontal cortex in schizophrenia and bipolar disorder (n = 55 cases and 27 controls). DNA methylation, transcriptomic, and genetic-epigenetic interactions in major psychosis converged on pathways of neurodevelopment, synaptic activity, and immune functions. We observe prominent hypomethylation of an enhancer within the insulin-like growth factor 2 (IGF2) gene in major psychosis neurons. Chromatin conformation analysis revealed that this enhancer targets the nearby tyrosine hydroxylase (TH) gene responsible for dopamine synthesis. In patients, we find hypomethylation of the IGF2 enhancer is associated with increased TH protein levels. In mice, Igf2 enhancer deletion disrupts the levels of TH protein and striatal dopamine, and induces transcriptional and proteomic abnormalities affecting neuronal structure and signaling. Our data suggests that epigenetic activation of the enhancer at IGF2 may enhance dopamine synthesis associated with major psychosis.
Na-doped ruthenium perovskite electrocatalysts with improved oxygen evolution activity and durability in acidic media
Authors: Retuerto María , Pascual Laura , Calle-Vallejo Federico , Ferrer Pilar , Gianolio Diego , Pereira Amaru González , García Álvaro , Torrero Jorge , Fernández-Díaz María Teresa , Bencok Peter , Peña Miguel A. , Fierro José Luis G. , Rojas Sergio
Published: May 2019

The design of active and durable catalysts for the H2O/O2 interconversion is one of the major challenges of electrocatalysis for renewable energy. The oxygen evolution reaction (OER) is catalyzed by SrRuO3 with low potentials (ca. 1.35 VRHE), but the catalyst’s durability is insufficient. Here we show that Na doping enhances both activity and durability in acid media. DFT reveals that whereas SrRuO3 binds reaction intermediates too strongly, Na doping of ~0.125 leads to nearly optimal OER activity. Na doping increases the oxidation state of Ru, thereby displacing positively O p-band and Ru d-band centers, weakening Ru-adsorbate bonds. The enhanced durability of Na-doped perovskites is concomitant with the stabilization of Ru centers with slightly higher oxidation states, higher dissolution potentials, lower surface energy and less distorted RuO6 octahedra. These results illustrate how high OER activity and durability can be simultaneously engineered by chemical doping of perovskites.
GWAS of bone size yields twelve loci that also affect height, BMD, osteoarthritis or fractures
Authors: Styrkarsdottir Unnur , Stefansson Olafur A. , Gunnarsdottir Kristbjorg , Thorleifsson Gudmar , Lund Sigrun H. , Stefansdottir Lilja , Juliusson Kristinn , Agustsdottir Arna B. , Zink Florian , Halldorsson Gisli H. , Ivarsdottir Erna V. , Benonisdottir Stefania , Jonsson Hakon , Gylfason Arnaldur , Norland Kristjan , Trajanoska Katerina , Boer Cindy G. , Southam Lorraine , Leung Jason C. S. , Tang Nelson L. S. , Kwok Timothy C. Y. , Lee Jenny S. W. , Ho Suzanne C. , Byrjalsen Inger , Center Jacqueline R. , Lee Seung Hun , Koh Jung-Min , Lohmander L. Stefan , Ho-Pham Lan T. , Nguyen Tuan V. , Eisman John A. , Woo Jean , Leung Ping-C. , Loughlin John , Zeggini Eleftheria , Christiansen Claus , Rivadeneira Fernando , van Meurs Joyce , Uitterlinden Andre G. , Mogensen Brynjolfur , Jonsson Helgi , Ingvarsson Thorvaldur , Sigurdsson Gunnar , Benediktsson Rafn , Sulem Patrick , Jonsdottir Ingileif , Masson Gisli , Holm Hilma , Norddahl Gudmundur L. , Thorsteinsdottir Unnur , Gudbjartsson Daniel F. , Stefansson Kari
Published: May 2019

Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans. In a GWA study of DXA bone area of the hip and lumbar spine (N ≥ 28,954), we find thirteen independent association signals at twelve loci that replicate in samples of European and East Asian descent (N = 13,608 – 21,277). Eight DXA area loci associate with osteoarthritis, including rs143384 in GDF5 and a missense variant in COL11A1 (rs3753841). The strongest DXA area association is with rs11614913[T] in the microRNA MIR196A2 gene that associates with lumbar spine area (P = 2.3 × 10−42, β = −0.090) and confers risk of hip fracture (P = 1.0 × 10−8, OR = 1.11). We demonstrate that the risk allele is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density.
Disruption of podocyte cytoskeletal biomechanics by dasatinib leads to nephrotoxicity
Authors: Calizo Rhodora C. , Bhattacharya Smiti , van Hasselt J. G. Coen , Wei Chengguo , Wong Jenny S. , Wiener Robert J. , Ge Xuhua , Wong Nicholas J. , Lee Jia-Jye , Cuttitta Christina M. , Jayaraman Gomathi , Au Vivienne H. , Janssen William , Liu Tong , Li Hong , Salem Fadi , Jaimes Edgar A. , Murphy Barbara , Campbell Kirk N. , Azeloglu Evren U.
Published: May 2019

Nephrotoxicity is a critical adverse event that leads to discontinuation of kinase inhibitor (KI) treatment. Here we show, through meta-analyses of FDA Adverse Event Reporting System, that dasatinib is associated with high risk for glomerular toxicity that is uncoupled from hypertension, suggesting a direct link between dasatinib and podocytes. We further investigate the cellular effects of dasatinib and other comparable KIs with varying risks of nephrotoxicity. Dasatinib treated podocytes show significant changes in focal adhesions, actin cytoskeleton, and morphology that are not observed with other KIs. We use phosphoproteomics and kinome profiling to identify the molecular mechanisms of dasatinib-induced injury to the actin cytoskeleton, and atomic force microscopy to quantify impairment to cellular biomechanics. Furthermore, chronic administration of dasatinib in mice causes reversible glomerular dysfunction, loss of stress fibers, and foot process effacement. We conclude that dasatinib induces nephrotoxicity through altered podocyte actin cytoskeleton, leading to injurious cellular biomechanics.
Social-ecological alignment and ecological conditions in coral reefs
Authors: Barnes Michele L. , Bodin Örjan , McClanahan Tim R. , Kittinger John N. , Hoey Andrew S. , Gaoue Orou G. , Graham Nicholas A. J.
Published: May 2019

Complex social-ecological interactions underpin many environmental problems. To help capture this complexity, we advance an interdisciplinary network modeling framework to identify important relationships between people and nature that can influence environmental conditions. Drawing on comprehensive social and ecological data from five coral reef fishing communities in Kenya; including interviews with 648 fishers, underwater visual census data of reef ecosystem condition, and time-series landings data; we show that positive ecological conditions are associated with ‘social-ecological network closure’ – i.e., fully linked and thus closed network structures between social actors and ecological resources. Our results suggest that when fishers facing common dilemmas form cooperative communication ties with direct resource competitors, they may achieve positive gains in reef fish biomass and functional richness. Our work provides key empirical insight to a growing body of research on social-ecological alignment, and helps to advance an integrative framework that can be applied empirically in different social-ecological contexts.
Integrating Hi-C and FISH data for modeling of the 3D organization of chromosomes
Authors: Abbas Ahmed , He Xuan , Niu Jing , Zhou Bin , Zhu Guangxiang , Ma Tszshan , Song Jiangpeikun , Gao Juntao , Zhang Michael Q. , Zeng Jianyang
Published: May 2019

The new advances in various experimental techniques that provide complementary information about the spatial conformations of chromosomes have inspired researchers to develop computational methods to fully exploit the merits of individual data sources and combine them to improve the modeling of chromosome structure. Here we propose GEM-FISH, a method for reconstructing the 3D models of chromosomes through systematically integrating both Hi-C and FISH data with the prior biophysical knowledge of a polymer model. Comprehensive tests on a set of chromosomes, for which both Hi-C and FISH data are available, demonstrate that GEM-FISH can outperform previous chromosome structure modeling methods and accurately capture the higher order spatial features of chromosome conformations. Moreover, our reconstructed 3D models of chromosomes revealed interesting patterns of spatial distributions of super-enhancers which can provide useful insights into understanding the functional roles of these super-enhancers in gene regulation.
Lnc-TALC promotes O6-methylguanine-DNA methyltransferase expression via regulating the c-Met pathway by competitively binding with miR-20b-3p
Authors: Wu Pengfei , Cai Jinquan , Chen Qun , Han Bo , Meng Xiangqi , Li Yansheng , Li Ziwei , Wang Ruijia , Lin Lin , Duan Chunbin , Kang Chunsheng , Jiang Chuanlu
Published: May 2019

Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules implicated in diverse biological processes, including therapeutic resistance. However, the mechanisms underlying lncRNA-mediated temozolomide (TMZ) resistance in glioblastoma (GBM) remain largely unknown. To illustrate the role of lncRNA in TMZ resistance, we induce TMZ-resistant GBM cells, perform a lncRNA microarray of the parental and TMZ-resistant cells, and find an unreported lncRNA in GBM, lnc-TALC (temozolomide-associated lncRNA in glioblastoma recurrence), correlated with TMZ resistance via competitively binding miR-20b-3p to facilitate c-Met expression. A phosphorylated AKT/FOXO3 axis regulated lnc-TALC expression in TMZ-resistant GBM cells. Furthermore, lnc-TALC increased MGMT expression by mediating the acetylation of H3K9, H3K27 and H3K36 in MGMT promoter regions through the c-Met/Stat3/p300 axis. In clinical patients, lnc-TALC is required for TMZ resistance and GBM recurrence. Our results reveal that lnc-TALC in GBM could serve as a therapeutic target to overcome TMZ resistance, enhancing the clinical benefits of TMZ chemotherapy.
Coral carbon isotope sensitivity to growth rate and water depth with paleo-sea level implications
Authors: Linsley Braddock K. , Dunbar Robert B. , Dassié Emilie P. , Tangri Neil , Wu Henry C. , Brenner Logan D. , Wellington Gerard M.
Published: May 2019

Although reef coral skeletal carbon isotopes (δ13C) are routinely measured, interpretation remains controversial. Here we show results of a consistent inverse relationship between coral δ13C and skeletal extension rate over the last several centuries in Porites corals at Fiji, Tonga, Rarotonga and American Samoa in the southwest Pacific. Beginning in the 1950s, this relationship breaks down as the atmospheric 13C Suess effect shifts skeletal δ13C > 1.0‰ lower. We also compiled coral δ13C from a global array of sites and find that mean coral δ13C decreases by −1.4‰ for every 5 m increase in water depth (R = 0.68, p < 0.01). This highlights the fundamental sensitivity of coral δ13C to endosymbiotic photosynthesis. Collectively, these results suggest that photosynthetic rate largely determines mean coral δ13C while changes in extension rate and metabolic effects over time modulate skeletal δ13C around this mean value. The newly quantified coral δ13C-water depth relationship may be an effective tool for improving the precision of paleo-sea level reconstruction using corals.
Microclot array elastometry for integrated measurement of thrombus formation and clot biomechanics under fluid shear
Authors: Chen Zhaowei , Lu Jiankai , Zhang Changjie , Hsia Isaac , Yu Xinheng , Marecki Leo , Marecki Eric , Asmani Mohammadnabi , Jain Shilpa , Neelamegham Sriram , Zhao Ruogang
Published: May 2019

Blood clotting at the vascular injury site is a complex process that involves platelet adhesion and clot stiffening/contraction in the milieu of fluid flow. An integrated understanding of the hemodynamics and tissue mechanics regulating this process is currently lacking due to the absence of an experimental system that can simultaneously model clot formation and measure clot mechanics under shear flow. Here we develop a microfluidic-integrated microclot-array-elastometry system (clotMAT) that recapitulates dynamic changes in clot mechanics under physiological shear. Treatments with procoagulants and platelet antagonists and studies with diseased patient plasma demonstrate the ability of the system to assay clot biomechanics associated with common antiplatelet treatments and bleeding disorders. The changes of clot mechanics under biochemical treatments and shear flow demonstrate independent yet equally strong effects of these two stimulants on clot stiffening. This microtissue force sensing system may have future research and diagnostic potential for various bleeding disorders.
Bacteroidetes use thousands of enzyme combinations to break down glycans
Authors: Lapébie Pascal , Lombard Vincent , Drula Elodie , Terrapon Nicolas , Henrissat Bernard
Published: May 2019

Unlike proteins, glycan chains are not directly encoded by DNA, but by the specificity of the enzymes that assemble them. Theoretical calculations have proposed an astronomical number of possible isomers (> 1012 hexasaccharides) but the actual diversity of glycan structures in nature is not known. Bacteria of the Bacteroidetes phylum are considered primary degraders of polysaccharides and they are found in all ecosystems investigated. In Bacteroidetes genomes, carbohydrate-degrading enzymes (CAZymes) are arranged in gene clusters termed polysaccharide utilization loci (PULs). The depolymerization of a given complex glycan by Bacteroidetes PULs requires bespoke enzymes; conversely, the enzyme composition in PULs can provide information on the structure of the targeted glycans. Here we group the 13,537 PULs encoded by 964 Bacteroidetes genomes according to their CAZyme composition. We find that collectively Bacteroidetes have elaborated a few thousand enzyme combinations for glycan breakdown, suggesting a global estimate of diversity of glycan structures much smaller than the theoretical one.
Coordination-driven self-assembly of a molecular figure-eight knot and other topologically complex architectures
Authors: Dang Li-Long , Sun Zhen-Bo , Shan Wei-Long , Lin Yue-Jian , Li Zhen-Hua , Jin Guo-Xin
Published: May 2019

Over the past decades, molecular knots and links have captivated the chemical community due to their promising mimicry properties in molecular machines and biomolecules and are being realized with increasing frequency with small molecules. Herein, we describe how to utilize stacking interactions and hydrogen-bonding patterns to form trefoil knots, figure-eight knots and [2]catenanes. A transformation can occur between the unique trefoil knot and its isomeric boat-shaped tetranuclear macrocycle by the complementary concentration effect. Remarkably, the realization and authentication of the molecular figure-eight knot with four crossings fills the blank about 41knot in knot tables. The [2]catenane topology is obtained because the selective naphthalenediimide (NDI)-based ligand, which can engender favorable aromatic donor-acceptor π interactions due to its planar, electron-deficient aromatic surface. The stacking interactions and hydrogen-bond interactions play important roles in these self-assembly processes. The advantages provide an avenue for the generation of structurally and topologically complex supramolecular architectures.
Cortical thinning in patients with REM sleep behavior disorder is associated with clinical progression
Authors: Pereira Joana B. , Weintraub Daniel , Chahine Lana , Aarsland Dag , Hansson Oskar , Westman Eric
Published: May 2019

The aim of this study is to determine whether structural MRI measures are associated with clinical impairment and progression to a Lewy body disease in patients with idiopathic REM sleep behavior disorder (iRBD). Twenty-seven patients with iRBD in addition to patients with de novo PD and healthy controls were included from the Parkinson’s Progression Markers Initiative. Patients with iRBD were followed for up to 3 years. Clinical and MRI measures were compared across groups and the association between clinical features and structural MRI was assessed in iRBD patients. Cox regression analyses were applied to identify risk factors for progressing to a Lewy body disease in iRBD. Our results showed that, at baseline, iRBD patients showed parietal and occipital cortical thinning, compared to controls. They also showed worse motor and non-motor abilities, some of which correlated with motor, frontal or temporal cortical thinning. At follow-up, six (22%) iRBD patients were diagnosed with a Lewy body disorder. These patients showed cortical thinning in frontal, occipital and parietal areas compared to iRBD non-converters. Cortical thinning was a significant predictor for future development of a Lewy body disorder (HR: 0.784; 95% CI: 0.640–0.960; p = 0.02). We conclude that cortical thinning is associated with worse motor and non-motor abilities, and predicts conversion to a Lewy body disorder in iRBD, suggesting it could be used to select candidates for clinical trials to delay the onset of neurodegenerative disease.
Asthma care based on Chronic Care Model in an aging Asian community
Authors: Zheng L. F. , Koh Y. L. E. , Sankari U. , Tan N. C.
Published: May 2019

To cope with the higher prevalence of asthma and other non-communicable diseases without compromising on quality of care, a Singapore public primary care institution has adopted the Chronic Care Model (CCM). This retrospective cohort study aimed to describe the proportion of patients with well-controlled asthma (based on Asthma Control Test score ≥20) between 2010 and 2016 in association with their management based on the CCM (which covers the polyclinic clinical information system, self-management measures, system re-design and decision support). Data were retrieved from the Singapore National Asthma Programme (SNAP) and institutional clinical quality databases of eight local polyclinics in eastern and southern Singapore. The data were aggregated, analysed and presented in proportions against monthly polyclinic attendances for asthma. From 2010 to 2016, the total asthma attendances increased by 31% from 27,345 to 35,731, with the highest rise among patients aged ≥60 years. The proportion of patients with good asthma control rose from 71.4% to 80.9%; those who received rescue therapy for acute exacerbations fell from 15.8% to 11.7% and those referred to emergency departments after failed rescue therapy decreased from 0.7% to 0.6%. The proportion of patients with updated asthma action plans increased from 66.7% to 73.4% (proxy for self-management). The overall health and process outcomes of asthma seemed to have improved with multiplex of system-based interventions relating to the introduction of CCM in a public primary healthcare institution in Singapore.
Differences in respiratory consultations in primary care between underweight, normal-weight, and overweight children
Authors: van Leeuwen Janneke , El Jaouhari Zoubeir , Paulis Winifred D. , Bindels Patrick J. E. , Koes Bart W. , van Middelkoop Marienke
Published: May 2019

This prospective cohort study investigates whether the suggested association between weight status and respiratory complaints in open populations is also reflected in the frequency of consultations for respiratory complaints at the general practice. Children aged 2–18 years presenting at one of the participating general practices in the Netherlands could be included. Electronic medical files were used to extract data on consultations. Logistic regression analyses and negative binomial regression analyses were used to assess the associations between weight status and the presence, and frequency of respiratory consultations, respectively, during 2-year follow-up. Subgroup analyses were performed in children aged 2–6, 6–12, and 12–18 years old. Of the 617 children, 115 (18.6%) were underweight, 391 (63.4%) were normal-weight, and 111 (18%) were overweight. Respiratory consultations were not more prevalent in underweight children compared to normal-weight children (odds ratio (OR) 0.87, 95% confidence inteval (CI) 0.64–1.10), and in overweight children compared to normal-weight children (OR 1.33, 95% CI 0.99–1.77). Overweight children aged 12–18 years had more respiratory consultations (OR 2.14, 95% CI 1.14–4.01), more asthma-like consultations (OR 3.94, 95%CI 1.20–12.88), and more respiratory allergy-related consultations (OR 3.14, 95% CI 1.25–7.86) than normal-weight children. General practitioners should pay attention to weight loss as part of the treatment of respiratory complaints in overweight and obese children.
Elementary excitation in the spin-stripe phase in quantum chains
Authors: Pregelj Matej , Zorko Andrej , Gomilšek Matjaž , Klanjšek Martin , Zaharko Oksana , White Jonathan S. , Luetkens Hubertus , Coomer Fiona , Ivek Tomislav , Rivas Góngora David , Berger Helmuth , Arčon Denis
Published: May 2019

Elementary excitations in condensed matter capture the complex many-body dynamics of interacting basic entities in a simple quasiparticle picture. In magnetic systems the most established quasiparticles are magnons, collective excitations that reside in ordered spin structures, and spinons, their fractional counterparts that emerge in disordered, yet correlated spin states. Here we report on the discovery of elementary excitation inherent to spin-stripe order that represents a bound state of two phason quasiparticles, resulting in a wiggling-like motion of the magnetic moments. We observe these excitations, which we dub “wigglons”, in the frustrated zigzag spin-1/2 chain compound β-TeVO4, where they give rise to unusual low-frequency spin dynamics in the spin-stripe phase. This result provides insights into the stripe physics of strongly-correlated electron systems.
Gelatin methacryloyl and its hydrogels with an exceptional degree of controllability and batch-to-batch consistency
Authors: Zhu Mengxiang , Wang Yingying , Ferracci Gaia , Zheng Jing , Cho Nam-Joon , Lee Bae Hoon
Published: May 2019

Gelatin methacryloyl (GelMA) is a versatile material for a wide range of bioapplications. There is an intense interest in developing effective chemical strategies to prepare GelMA with a high degree of batch-to-batch consistency and controllability in terms of methacryloyl functionalization and physiochemical properties. Herein, we systematically investigated the batch-to-batch reproducibility and controllability of producing GelMA (target highly and lowly substituted versions) via a one-pot strategy. To assess the GelMA product, several parameters were evaluated, including the degree of methacryloylation, secondary structure, and enzymatic degradation, along with the mechanical properties and cell viability of GelMA hydrogels. The results showed that two types of target GelMA with five batches exhibited a high degree of controllability and reproducibility in compositional, structural, and functional properties owing to the highly controllable one-pot strategy.