bluuebunny/crossref_metadata_2025 huggingface dataset:
Multivalency of NDC80 in the outer kinetochore is essential to track shortening microtubules and generate forces
Authors: Volkov Vladimir A , Huis in 't Veld Pim J , Dogterom Marileen , Musacchio Andrea
Published: April 2018

Presence of multiple copies of the microtubule-binding NDC80 complex is an evolutionary conserved feature of kinetochores, points of attachment of chromosomes to spindle microtubules. This may enable multivalent attachments to microtubules, with implications that remain unexplored. Using recombinant human kinetochore components, we show that while single NDC80 complexes do not track depolymerizing microtubules, reconstituted particles containing the NDC80 receptor CENP-T bound to three or more NDC80 complexes do so effectively, as expected for a kinetochore force coupler. To study multivalency systematically, we engineered modules allowing incremental addition of NDC80 complexes. The modules’ residence time on microtubules increased exponentially with the number of NDC80 complexes. Modules with two or more complexes tracked depolymerizing microtubules with increasing efficiencies, and stalled and rescued microtubule depolymerization in a force-dependent manner when conjugated to cargo. Our observations indicate that NDC80, rather than through biased diffusion, tracks depolymerizing microtubules by harnessing force generated during microtubule disassembly.
Communities creating change
Authors: Kuehn Bridget M
Published: April 2018

Women scientists across India are working together to build and advocate for family-friendly policies at their institutes.
Genetic divergence and fine scale population structure of the common bottlenose dolphin (Tursiops truncatus, Montagu) found in the Gulf of Guayaquil, Ecuador
Authors: Bayas-Rea Rosa de los Ángeles , Félix Fernando , Montufar Rommel
Published: April 2018

The common bottlenose dolphin,Tursiops truncatus, is widely distributed along the western coast of South America. In Ecuador, a resident population of bottlenose dolphins inhabits the inner estuarine area of the Gulf of Guayaquil located in the southwestern part of the country and is under threat from different human activities in the area. Only one genetic study on South American common bottlenose dolphins has been carried out to date, and understanding genetic variation of wildlife populations, especially species that are identified as threatened, is crucial for defining conservation units and developing appropriate conservation strategies. In order to evaluate the evolutionary link of this population, we assessed the phylogenetic relationships, phylogeographic patterns, and population structure using mitochondrial DNA (mtDNA). The sampling comprised: (i) 31 skin samples collected from free-ranging dolphins at three locations in the Gulf of Guayaquil inner estuary, (ii) 38 samples from stranded dolphins available at the collection of the “Museo de Ballenas de Salinas,” (iii) 549 mtDNA control region (mtDNA CR) sequences from GenBank, and (iv) 66 concatenated sequences from 7-mtDNA regions (12S rRNA,16S rRNA, NADH dehydrogenase subunit I–II, cytochrome oxidase I and II, cytochrome b, and CR) obtained from mitogenomes available in GenBank. Our analyses indicated population structure between both inner and outer estuary dolphin populations as well as with distinct populations ofT. truncatususing mtDNA CR. Moreover, the inner estuary bottlenose dolphin (estuarine bottlenose dolphin) population exhibited lower levels of genetic diversity than the outer estuary dolphin population according to the mtDNA CR. Finally, the estuarine bottlenose dolphin population was genetically distinct from otherT. truncatuspopulations based on mtDNA CR and 7-mtDNA regions. From these results, we suggest that the estuarine bottlenose dolphin population should be considered a distinct lineage. This dolphin population faces a variety of anthropogenic threats in this area; thus, we highlight its fragility and urge authorities to issue prompt management and conservation measures.
Coccolith arrangement follows Eulerian mathematics in the coccolithophoreEmiliania huxleyi
Authors: Xu Kai , Hutchins David , Gao Kunshan
Published: April 2018

Background

The globally abundant coccolithophore,Emiliania huxleyi, plays an important ecological role in oceanic carbon biogeochemistry by forming a cellular covering of plate-like CaCO3crystals (coccoliths) and fixing CO2. It is unknown how the cells arrange different-sized coccoliths to maintain full coverage, as the cell surface area of the cell changes during daily cycle.

Methods

We used Euler’s polyhedron formula and CaGe simulation software, validated with the geometries of coccoliths, to analyze and simulate the coccolith topology of the coccosphere and to explore the arrangement mechanisms.

Results

There were only small variations in the geometries of coccoliths, even when the cells were cultured under variable light conditions. Because of geometric limits, small coccoliths tended to interlock with fewer and larger coccoliths, and vice versa. Consequently, to sustain a full coverage on the surface of cell, each coccolith was arranged to interlock with four to six others, which in turn led to each coccosphere contains at least six coccoliths.

Conclusion

The number of coccoliths per coccosphere must keep pace with changes on the cell surface area as a result of photosynthesis, respiration and cell division. This study is an example of natural selection following Euler’s polyhedral formula, in response to the challenge of maintaining a CaCO3covering on coccolithophore cells as cell size changes.
Crescimento e desigualdade no nordeste do Brasil: 2002-2006
Authors: Marques André M
Published: April 2018

A partir de uma base de dados municipal, com caráter exploratório, o principal objetivo do estudo foi investigar se houve diferenças significativas no crescimento econômico e no grau de desigualdade de renda entre os estados da região Nordeste do Brasil no período 2002-2006. A metodologia empregada baseou-se no teste Kruskal-Wallis e no teste U de Wilcoxon-Mann-Whitney. Os resultados indicam a existência de diferenças estatisticamente significativas no crescimento e no grau de desigualdade entre os estados da região. Foi possível detectar uma hierarquia para o crescimento e a desigualdade entre os estados do Nordeste. No geral, os resultados encontrados indicam uma correlação linear inversa entre crescimento e desigualdade estatisticamente significativa nos municípios da Paraíba, Ceará e Alagoas. Há indícios de convergência de renda apenas nos estados da Paraíba e Pernambuco.
O comércio internacional como promotor de crescimento econômico o caso da América do Sul
Authors: Feler Rafael Dornelles
Published: April 2018

Neste trabalho procura-se observar a relação entre o comércio internacional de bens e serviços e o crescimento econômico das nações, buscando questionar se o comércio internacional funciona como promotor de crescimento econômico. Após breve descrição das teorias nas quais se baseiam a maioria dos trabalhos sobre o tema, observa-se a ausência de resultados conclusivos em observações empíricas tanto quanto à intensidade quanto à causalidade da relação analisada. A partir da observação histórica e do estudo do caso das economias da América do Sul, concluise então ser a política comercial uma ferramenta econômica para a promoção do crescimento econômico, a ser usada da maneira como for requerida pelo contexto externo e a situação macroeconômica interna, estando suscetível a mudanças ao longo do tempo.
Desconcentração e interiorização da economia fluminense no período de 1996 a 2005
Authors: Souza Paulo M , Ponciano Niraldo José , Ney Marlon Gomes , Mata Henrique Tomé da Costa
Published: April 2018

O objetivo da pesquisa foi analisar o processo de desconcentração e interiorização da economia do Estado do Rio de Janeiro na última década, mais especificamente o período de 1996 a 2005. Com o uso do modelo estrutural diferencial, fez-se uma análise da evolução do pessoal ocupado nas diversas mesorregiões geográficas que compõem o Estado, considerando-se as atividades: indústria extrativa mineral, indústria de transformação, servi-ços industriais de utilidade pública, indústria da construção civil, comércio, serviços, administração pública e agropecuária. Os resultados evidenciaram a ocorrência de desconcentração industrial, com redução da participação da região metropolitana no emprego e na renda, o que se deve, principalmente, à expansão da indústria extrativa mineral associada ao petróleo.
ARCO-ÍRIS NO CAMPO: ETNOGRAFIA DA “HOMOSSEXUALIDADE” MASCULINA NO AMBIENTE RURAL
Authors: Azevedo Pedro Henrique
Published: April 2018

O ambiente rural caracteriza-se por uma região não urbanizada. É o campo em contraponto com a cidade. A zona rural sempre foi classificada como um ambiente repressor e conservador, já a cidade tem como características o anonimato e a liberdade. Na lógica que a heterossexualidade é normatizada em todos os ambientes, uma comunidade campal tem enraizada questões como o machismo e a heteronormatividade de forma mais intensa que o ambiente urbano, por conta de questões geográficas e de valores socioculturais. Contudo, existe uma alegação que em comunidades rurais há uma consumação de práticas sexuais entre adolescentes homens, ou seja, uma prática sexual gay durante a puberdade masculina. A pesquisa em tela busca comprovar a existência destas práticas “homossexuais”, bem como interpretar a dinâmica que as envolvem a fim de compreender como se performatiza a identidade social destes moços. Tendo por base a etnografia, foi realizada uma pesquisa de campo, nos moldes tradicionais da observação participante de cunho antropológico, durante três meses de intenso convívio social na comunidade camponesa Olhos Cristais (nome fictício) do município de Baraúna/RN, em que se observou toda a conjuntura expressa através do cotidiano por diversos momentos e espaços de sociabilidade. Também foram realizadas conversas individuais com quatro rapazes. Os rapazes tinham de 19 a 23 anos de idade, e através da história oral fizeram todo um resgate do aspecto estudado, no que diz respeito à vivencia particular de cada um. De fato, as práticas sexuais e afetivas entre rapazes da zona rural existem e não estão concentradas apenas na adolescência, pois se expressam também até a fase adulta da vida, como foi perceptível. Pensar estas práticas é compreender um mundo de dupla face, onde o âmbito particular e o público assumem formas muitas vezes contrastantes, demonstrando um poder influente e coercitivo da sociedade no processo de construção performativa da identidade deles, em que os rapazes se moldam aos valores e costumes nativos a fim de obter uma convivência pacífica e longe de preconceitos, assumindo uma identidade às vezes contraditória, mas nunca deixando de usufruir dos variados prazeres da vida.
A Banca de verificação da auto declaração étnico racial do vestibular 2010 da Universidade Federal do Paraná: notas etnográficas
Authors: SILVEIRA MARCOS SILVA
Published: April 2018

Esta etnografia procura apresentar os momentos mais significativos da Banca de verificação da auto declaração étnico racial do vestibular da UFPR, no ano de 2010, enquanto vigorava o padrão de Cota e Banca racial local. Esse tipo de banca foi alvo de muitas controvérsias por onde existiu. Procuro apontar que as questões envolvendo a auto identificação racial e seu reconhecimento por uma banca da Universidade caminhavam em direções distintas do que o debate sobre as mesmas e seu críticos queriam apontar.
Signature‐Domain Calibration of Hydrological Models Using Approximate Bayesian Computation: Empirical Analysis of Fundamental Properties
Authors: Fenicia Fabrizio , Kavetski Dmitri , Reichert Peter , Albert Carlo
Published: April 2018

This study investigates Bayesian signature‐domain inference of hydrological models using Approximate Bayesian Computation (ABC) algorithms, and compares it to “traditional” time‐domain inference. Our focus is on the quantification of predictive uncertainty in the streamflow time series and on understanding the information content of particular combinations of signatures. A combination of synthetic and real data experiments using conceptual rainfall‐runoff models is employed. Synthetic experiments demonstrate: (i) the general consistency of signature and time‐domain inferences, (ii) the ability to estimate streamflow error model parameters (reliably quantify streamflow uncertainty) even when calibrating in the signature domain, and (iii) the potential robustness of signature‐domain inference when the (probabilistic) hydrological model is misspecified (e.g., by unaccounted timing errors). The experiments also suggest limitations of the signature‐domain approach in terms of information loss when general (nonsufficient) statistics are used, and increased computational costs incurred by the ABC implementation. Real data experiments confirm the viability of Bayesian signature‐domain inference and its general consistency with time‐domain inference in terms of predictive uncertainty quantification. In addition, we demonstrate the utility of the flashiness index for the estimation of streamflow error parameters, and show that signatures based on the Flow Duration Curve alone are insufficient to calibrate parameters controlling streamflow dynamics. Overall, the study further establishes signature‐domain inference (implemented using ABC) as a promising method for comparing the information content of hydrological signatures, for prediction under data‐scarce conditions, and, under certain circumstances, for mitigating the impact of deficiencies in the formulation of the predictive model.
Using Tidal Fluctuation‐Induced Dynamics of Radium Isotopes (224Ra, 223Ra, and 228Ra) to Trace the Hydrodynamics and Geochemical Reactions in a Coastal Groundwater Mixing Zone
Authors: Liu Yi , Jiao Jiu Jimmy , Liang Wenzhao , Luo Xin
Published: April 2018

The reactive transport of radium isotopes (224Ra, 223Ra, and 228Ra) in coastal groundwater mixing zones (CGMZs) is sensitive to shifts of redox conditions and geochemical reactions induced by tidal fluctuation. This study presents a spatial distribution and temporal variation of radium isotopes in the CGMZ for the first time. Results show that the activity of radium isotopes in the upper saline plume (USP) is comparatively low due to a short residence time and mixing loss induced by the infiltration of low radium seawater whereas the activity of radium isotopes in the salt wedge (SW) is comparatively high due to a long residence time in the aquifer. The spatial distribution of radium isotopes is determined by the partitioning of radium isotopes, groundwater residence time, and relative ingrowth rates of radium isotopes. In addition, the variation of radium isotopes in the USP lags slightly (∼0 h) whereas the fluctuation of radium isotopes in the SW lags significantly (∼12 h) behind sea level oscillation. Tidal fluctuation affects the partitioning of radium isotopes through controlling seawater infiltration and subsequently influences the dynamics of radium isotopes in the USP. Concurrently, seawater infiltration significantly affects geochemical processes such as the production of nutrients and total alkalinity. Therefore, radium dynamics in the USP have implications for these geochemical processes. The variation of radium isotopes in the USP also has potential implications for transformation of trace metals such as iron and manganese because of the close affinity of radium isotopes to manganese and iron oxides.
The best of both worlds? A review of delayed selfing in flowering plants
Authors: Goodwillie Carol , Weber Jennifer J.
Published: April 2018

Premise of Study

In a seminal body of theory, Lloyd showed that the fitness consequences of selfing will depend on its timing in anthesis. Selfing that occurs after opportunities for outcrossing or pollen dispersal can provide reproductive assurance when pollinators are limited and is expected to incur little cost, even when inbreeding depression is high. As a result, delayed selfing is often interpreted as a “best‐of‐both‐worlds” mating system that combines the advantages of selfing and outcrossing.

Methods

We surveyed 65 empirical studies of delayed selfing, recording floral mechanisms and examining information on inbreeding depression, autofertility, and other parameters to test the support for delayed selfing as a best‐of‐both‐worlds strategy.

Key Results

Phylogenetic distribution of the diverse floral mechanisms suggests that some basic floral structures may predispose plant taxa to evolve delayed selfing. Delayed selfing appears to serve as a best‐of‐both‐worlds strategy in some but not all species. While the capacity for autonomous selfing is often high, it is lower, in some cases, than in related species with earlier modes of selfing. In other delayed‐selfers, low inbreeding depression and reduced investment in corollas and pollen suggest limited benefits from outcrossing.

Conclusions

Despite a growing literature on the subject, experimental evidence for delayed selfing is limited and major gaps in knowledge remain, particularly with respect to the stability of delayed selfing and the conditions that may favor transitions between delayed and earlier selfing. Finally, we suggest a potential role of delayed selfing in facilitating transitions from self‐incompatibility to selfing.
The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant
Authors: Chatron Nicolas , Møller Rikke S. , Champaigne Neena L. , Schneider Amy L. , Kuechler Alma , Labalme Audrey , Simonet Thomas , Baggett Lauren , Bardel Claire , Kamsteeg Erik‐Jan , Pfundt Rolph , Romano Corrado , Aronsson Johan , Alberti Antonino , Vinci Mirella , Miranda Maria J. , Lacroix Amy , Marjanovic Dragan , des Portes Vincent , Edery Patrick , Wieczorek Dagmar , Gardella Elena , Scheffer Ingrid E. , Mefford Heather , Sanlaville Damien , Carvill Gemma L. , Lesca Gaetan
Published: April 2018

Objective

Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching, spine development, and synapse formation in layer II to III neurons of the cerebral cortex. We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE).

Methods

The de novo p.Glu590Lys variant was identified by whole‐exome sequencing (n = 5) or targeted gene panel (n = 4). We performed electroclinical and imaging phenotyping on all patients.

Results

The cohort comprised 7 males and 2 females. Mean age at study was 13 years (0.5–21.0). Median age at seizure onset was 6 months (2 months to 9 years). Seizure types at onset were myoclonic, atypical absence with myoclonic components, and focal seizures. Epileptiform activity on electroencephalogram was seen in 8 cases: generalized polyspike‐wave (6) or multifocal discharges (2). Seizures were drug resistant in 7 or controlled with valproate (2). Six patients had a DEE: myoclonic DEE (3), Lennox‐Gastaut syndrome (2), and West syndrome (1). Two had a static encephalopathy and genetic generalized epilepsy, including absence epilepsy in 1. One infant had multifocal epilepsy. Eight had severe cognitive impairment, with autistic features in 6. The p.Glu590Lys variant affects a highly conserved glutamine residue in the CUT domain predicted to interfere with CUX2 binding to DNA targets during neuronal development.

Interpretation

Patients with CUX2 p.Glu590Lys display a distinctive phenotypic spectrum, which is predominantly generalized epilepsy, with infantile‐onset myoclonic DEE at the severe end and generalized epilepsy with severe static developmental encephalopathy at the milder end of the spectrum. Ann Neurol 2018;83:926–934
Modeled De Facto Reuse and Contaminants of Emerging Concern in Drinking Water Source Waters
Authors: Nguyen Thuy , Westerhoff Paul , Furlong Edward T. , Kolpin Dana W. , Batt Angela L. , Mash Heath E. , Schenck Kathleen M. , Boone J. Scott , Rice Jacelyn , Glassmeyer Susan T.
Published: April 2018

De facto reuse is the percentage of drinking water treatment plant (DWTP) intake potentially composed of effluent discharged from upstream wastewater treatment plants (WWTPs). Results from grab samples and a De Facto Reuse in our Nation's Consumable Supply (DRINCS) geospatial watershed model were used to quantify contaminants of emerging concern (CECs) concentrations at DWTP intakes to qualitatively compare exposure risks obtained by the two approaches. Between nine and 71 CECs were detected in grab samples. The number of upstream WWTP discharges ranged from 0 to >1,000; comparative de facto reuse results from DRINCS ranged from <0.1 to 13% during average flow and >80% during lower streamflows. Correlation between chemicals detected and DRINCS modeling results were observed, particularly DWTPs withdrawing from midsize water bodies. This comparison advances the utility of DRINCS to identify locations of DWTPs for future CEC sampling and treatment technology testing.
Preparing for Change: TCP Overview and Treatment Considerations
Authors: Porter Katie Leo , Mackey Erin D.
Published: April 2018

California and Hawaii each have adopted a maximum contaminant level for 1,2,3‐trichloropropane (TCP) in drinking water, and other states have developed guidance for TCP; treatment of this emerging contaminant warrants careful consideration.
Water Costs and Affordability in the United States: 1990 to 2015
Authors: Rubin Scott J.
Published: April 2018

Nearly 25 years after the D/Dbp negotiations focused attention on affordability, it is now a good time to examine how the cost and affordability of water service in the United States have changed.
γ‐Herringbone Polymorph of 6,13‐Bis(trimethylsilylethynyl)pentacene: A Potential Material for Enhanced Hole Mobility
Authors: Bhat Vinayak , Gopan Gopika , Nair Nanditha G. , Hariharan Mahesh
Published: April 2018

The introduction of the trialkylsilylethynyl group to the acene core is known to predominantly transform the herringbone structure of pentacene to a slip‐stacked packing. However, herein, the occurrence of an unforeseen polymorph of 6,13‐bis(trimethylsilylethynyl)pentacene (TMS‐pentacene), with an atypical γ‐herringbone packing arrangement, is reported. Intermolecular noncovalent interactions in the γ‐herringbone polymorph are determined from Hirshfeld surface and quantum theory of atoms‐in‐molecules (QTAIM) analyses. Furthermore, a comparative truncated symmetry‐adapted perturbation theory (SAPT(0)) energy decomposition analysis discloses the role of exchange repulsions that govern molecular packing in the γ‐herringbone polymorph. Moreover, the computationally predicted electronic coupling and anisotropic mobility reveal the possibility of enhanced hole transport (μh=3.7 cm2 V−1 s−1) in the γ‐herringbone polymorph, in contrast to the reported polymorph with a hole mobility ofμh=0.1 cm2 V−1 s−1.
Dasatinib dose management for the treatment of chronic myeloid leukemia
Authors: Talpaz Moshe , Saglio Giuseppe , Atallah Ehab , Rousselot Philippe
Published: April 2018

Chronic myeloid leukemia (CML) has evolved into a chronic disease that is managed with tyrosine kinase inhibitor therapy. Now that long‐term survival has been achieved in patients with CML, the focus of treatment has shifted to dose optimization, with the goal of maintaining response while improving quality of life. In this review, the authors discuss optimizing the dose of the second‐generation tyrosine kinase inhibitor dasatinib. Once‐daily dosing regimens for dasatinib in the first and later lines of treatment were established through long‐term (5‐year and 7‐year) trials. Recently published data have indicated that further dose optimization may maintain efficacy while minimizing adverse events. Results obtained from dose optimization and discontinuation trials currently in progress will help practitioners determine the best dose and duration of dasatinib for patients with CML, because treatment decisions will be made through continued discussions between physicians and patients. Cancer 2018;124:1660‐72. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Exploring the Genetic Landscape of Metabolic Phenotypes with MetaboSignal
Authors: Rodriguez‐Martinez Andrea , Ayala Rafael , Posma Joram M. , Dumas Marc‐Emmanuel
Published: April 2018

MetaboSignal is an R/Bioconductor package designed to explore the relationships between genes and metabolites, using the Kyoto Encyclopedia of Genes and Genomes (KEGG) as its primary database. It is a network‐based approach that allows overlaying metabolic and signaling pathways and exploring the topological relationship between genes (signaling or metabolic genes) and metabolites. MetaboSignal is ideally suited to identify candidate genes in metabolome genome‐wide association studies (mGWAS), particularly in the case of trans‐acting associations. It can also be used to provide mechanistic explanations of perturbed metabolic patterns observed in genetic models, as well as to identify novel target metabolic pathways of signaling genes. © 2018 by John Wiley & Sons, Inc.
Leveraging Experimental Details for an Improved Understanding of Host‐Pathogen Interactome
Authors: Ammari Mais , McCarthy Fiona , Nanduri Bindu
Published: April 2018

An increasing proportion of curated host‐pathogen interaction (HPI) information is becoming available in interaction databases. These data represent detailed, experimentally‐verified, molecular interaction data, which may be used to better understand infectious diseases. By their very nature, HPIs are context dependent, where the outcome of two proteins as interacting or not depends on the precise biological conditions studied and approaches used for identifying these interactions. The associated biology and the technical details of the experiments identifying interacting protein molecules are increasing being curated using defined curation standards but are overlooked in current HPI network modeling. Given the increase in data size and complexity, awareness of the process and variables included in HPI identification and curation, and their effect on data analysis and interpretation is crucial in understanding pathogenesis. We describe the use of HPI data for network modeling, aspects of curation that can help researchers to more accurately model specific infection conditions, and provide examples to illustrate these principles. © 2018 by John Wiley & Sons, Inc.
Visualizing Autophagic Lysosome Reformation in Cells Using In Vitro Reconstitution Systems
Authors: Chen Yang , Su Qian Peter , Sun Yujie , Yu Li
Published: April 2018

Autophagy is a lysosome‐based degradation pathway. Autophagic lysosome reformation (ALR) is a lysosomal membrane recycling process that marks the terminal step of autophagy. During ALR, LAMP1‐positive tubules, named reformation tubules, are extruded from autolysosomes, and nascent lysosomes are generated from these tubules. By combining proteomic analysis of purified autolysosomes and RNA interference screening of identified candidates, we systematically elucidated the ALR pathway at the molecular level. Based on the key components clathrin, PtdIns(4,5)P2, and the motor protein KIF5B, among others, we reconstituted this process in vitro. This unit describes a detailed method for visualizing ALR in cells during the autophagy process. This unit also present a protocol for reconstituting the ALR tubular protrusion and elongation process in vitro and three methods for preparing materials for in vitro reconstitution: (1) autolysosome purification from cultured cells, (2) liposome preparation, and (3) KIF5B purification and quality testing. © 2018 by John Wiley & Sons, Inc.
Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis
Authors: van der Windt Dirk J. , Sud Vikas , Zhang Hongji , Varley Patrick R. , Goswami Julie , Yazdani Hamza O. , Tohme Samer , Loughran Patricia , O'Doherty Robert M. , Minervini Marta I. , Huang Hai , Simmons Richard L. , Tsung Allan
Published: April 2018

Nonalcoholic steatohepatitis (NASH) is a progressive, inflammatory form of fatty liver disease. It is the most rapidly rising risk factor for the development of hepatocellular carcinoma (HCC), which can arise in NASH with or without cirrhosis. The inflammatory signals promoting the progression of NASH to HCC remain largely unknown. The propensity of neutrophils to expel decondensed chromatin embedded with inflammatory proteins, known as neutrophil extracellular traps (NETs), has been shown to be important in chronic inflammatory conditions and in cancer progression. In this study, we asked whether NET formation occurs in NASH and contributes to the progression of HCC. We found elevated levels of a NET marker in serum of patients with NASH. In livers from STAM mice (NASH induced by neonatal streptozotocin and high‐fat diet), early neutrophil infiltration and NET formation were seen, followed by an influx of monocyte‐derived macrophages, production of inflammatory cytokines, and progression of HCC. Inhibiting NET formation, through treatment with deoxyribonuclease (DNase) or using mice knocked out for peptidyl arginine deaminase type IV (PAD4−/−), did not affect the development of a fatty liver but altered the consequent pattern of liver inflammation, which ultimately resulted in decreased tumor growth. Mechanistically, we found that commonly elevated free fatty acids stimulate NET formation in vitro. Conclusion: Our findings implicate NETs in the protumorigenic inflammatory environment in NASH, suggesting that their elimination may reduce the progression of liver cancer in NASH. (Hepatology 2018).
Disruption of Renal Arginine Metabolism Promotes Kidney Injury in Hepatorenal Syndrome in Mice
Authors: Varga Zoltan V. , Erdelyi Katalin , Paloczi Janos , Cinar Resat , Zsengeller Zsuzsanna K. , Jourdan Tony , Matyas Csaba , Nemeth Balazs Tamas , Guillot Adrien , Xiang Xiaogang , Mehal Adam , Haskó György , Stillman Isaac E. , Rosen Seymour , Gao Bin , Kunos George , Pacher Pal
Published: April 2018

Tubular dysfunction is an important feature of renal injury in hepatorenal syndrome (HRS) in patients with end‐stage liver disease. The pathogenesis of kidney injury in HRS is elusive, and there are no clinically relevant rodent models of HRS. We investigated the renal consequences of bile duct ligation (BDL)‐induced hepatic and renal injury in mice in vivo by using biochemical assays, real‐time polymerase chain reaction (PCR), Western blot, mass spectrometry, histology, and electron microscopy. BDL resulted in time‐dependent hepatic injury and hyperammonemia which were paralleled by tubular dilation and tubulointerstitial nephritis with marked upregulation of lipocalin‐2, kidney injury molecule 1 (KIM‐1) and osteopontin. Renal injury was associated with dramatically impaired microvascular flow and decreased endothelial nitric oxide synthase (eNOS) activity. Gene expression analyses signified proximal tubular epithelial injury, tissue hypoxia, inflammation, and activation of the fibrotic gene program. Marked changes in renal arginine metabolism (upregulation of arginase‐2 and downregulation of argininosuccinate synthase 1), resulted in decreased circulating arginine levels. Arginase‐2 knockout mice were partially protected from BDL‐induced renal injury and had less impairment in microvascular function. In human‐cultured proximal tubular epithelial cells hyperammonemia per se induced upregulation of arginase‐2 and markers of tubular cell injury. Conclusion: We propose that hyperammonemia may contribute to impaired renal arginine metabolism, leading to decreased eNOS activity, impaired microcirculation, tubular cell death, tubulointerstitial nephritis and fibrosis. Genetic deletion of arginase‐2 partially restores microcirculation and thereby alleviates tubular injury. We also demonstrate that BDL in mice is an excellent, clinically relevant model to study the renal consequences of HRS. (Hepatology 2018; 00:000‐000).
Prospective cohort study comparing outcomes between vacuum extraction and second‐stage cesarean delivery at a Ugandan tertiary referral hospital
Authors: Nolens Barbara , Namiiro Flavia , Lule John , van den Akker Thomas , van Roosmalen Jos , Byamugisha Josaphat
Published: April 2018

Objective

To compare maternal and perinatal outcomes between vacuum extraction and second‐stage cesarean delivery (SSCD).

Methods

The present observational cohort study was conducted among women with term vertex singleton pregnancies who underwent vacuum extraction or SSCD at Mulago National Referral Hospital, Kampala, Uganda, between November 25, 2014, and July 8, 2015. Severe maternal outcomes (mortality, uterine rupture, hysterectomy, re‐laparotomy) and perinatal outcomes (mortality, trauma, low Apgar score, convulsions) were compared between initial delivery mode.

Results

Among 13 152 deliveries, 358 women who underwent vacuum extraction and 425 women who underwent SSCD were enrolled in the study. No maternal deaths occurred after vacuum extraction versus five deaths from complications of SSCD. Vacuum extraction was associated with less severe maternal outcomes compared with SSCD (3 [0.8%] vs 18 [4.2%]; adjusted odds ratio [aOR] 0.24, 95% confidence interval [CI] 0.07–0.84). Fetal death during the decision‐to‐delivery interval was also less common in the vacuum extraction group (3 [0.9%] vs 18 [4.4%]; aOR 0.24, 95% CI 0.07–0.84); however, the perinatal mortality rate did not differ between the vacuum extraction and SSCD groups (29 [8.4%] vs 45 [11.0%], respectively; aOR 0.83, 95% CI 0.49–1.41). One infant in each group exhibited neurodevelopmental anomalies at 6 months.

Conclusion

Vacuum extraction had better maternal outcomes and equivalent perinatal outcomes compared with SSCD. These findings encourage re‐introduction of vacuum extraction.
Long non‐coding RNA SNHG15 promotes CDK14 expression via miR‐486 to accelerate non‐small cell lung cancer cells progression and metastasis
Authors: Jin Bing , Jin Hua , Wu Hai‐Bo , Xu Jian‐Jun , Li Bing
Published: April 2018

Long non‐coding RNAs (lncRNAs) have been validated to play important role in multiple cancers, including non‐small cell lung cancer (NSCLC). In present study, our team investigate the biologic role of SNHG15 in the NSCLC tumorigenesis. LncRNA SNHG15 was significantly upregulated in NSCLC tissue samples and cells, and its overexpression was associated with poor prognosis of NSCLC patients. In vitro, loss‐of‐functional cellular experiments showed that SNHG15 silencing significantly inhibited the proliferation, promoted the apoptosis, and induced the cycle arrest at G0//G1 phase. In vivo, xenograft assay showed that SNHG15 silencing suppressed tumor growth of NSCLC cells. Besides, SNHG15 silencing decreased CDK14 protein expression both in vivo and vitro. Bioinformatics tools and luciferase reporter assay confirmed that miR‐486 both targeted the 3′‐UTR of SNHG15 and CDK14 and was negatively correlated with their expression levels. In summary, our study conclude that the ectopic overexpression of SNHG15 contribute to the NSCLC tumorigenesis by regulating CDK14 protein via sponging miR‐486, providing a novel insight for NSCLC pathogenesis and potential therapeutic strategy for NSCLC patients.
Structural insights into suppressor of cytokine signaling 1 protein‐ identification of new leads for type 2 diabetes mellitus
Authors: Dumpati Ramakrishna , Ramatenki Vishwanath , Vadija Rajender , Vellanki Santhiprada , Vuruputuri Uma
Published: April 2018

The study considers the Suppressor of cytokine signaling 1 (SOCS1) protein as a novel Type 2 diabetes mellitus (T2DM) drug target. T2DM in human beings is also triggered by the over expression of SOCS proteins. The SOCS1 acts as a ubiquitin ligase (E3), degrades Insulin Receptor Substrate 1 and 2 (IRS1 and IRS2) proteins, and causes insulin resistance. Therefore, the structure of the SOCS1 protein was evaluated using homology‐modeling and molecular dynamics methods and validated using standard computational protocols. The Protein‐Protein docking study of SOCS1 with its natural substrates, IRS1 and IRS2, and subsequent solvent accessible surface area analysis gave insight into the binding region of the SOCS1 protein. The in silico active site prediction tools highlight the residues Val155 to Ile211 in SOCS1 being implicated in the ubiquitin mediated protein degradation of the proteins IRS1 and IRS2. Virtual screening in the active site region, using large structural databases, results in selective lead structures with 3‐Pyridinol, Xanthine, and Alanine moieties as Pharmacophore. The virtual screening study shows that the residues Glu149, Gly187, Arg188, Leu191, and Ser205 of the SOCS1 are important for binding. The docking study with current anti‐diabetic therapeutics shows that the drugs Glibenclamide and Glyclopyramide have a partial affinity towards SOCS1. The predicted ADMET and IC50 properties for the identified ligands are within the acceptable range with drug‐like properties. The structural data of SOCS1, its active site, and the identified lead structures are expedient in the development of new T2DM therapeutics.
Epitope imprinting of iron binding protein of Neisseria meningitidis bacteria through multiple monomers imprinting approach
Authors: Gupta Neha , Singh Roop Shikha , Shah Kavita , Prasad Rajniti , Singh Meenakshi
Published: April 2018

Epitope imprinting is a promising technique for fabrication of novel diagnostic tools. In this study, an epitope imprinted methodology for recognition of target epitope sequence as well as targeted protein infused by bacterial infection in blood samples of patients suffering from brain fever is developed. Template sequence chosen is a ferric iron binding fbp A protein present in Neisseria meningitidis bacteria. To orient the imprinting template peptide sequence on gold surface of electrochemical quartz crystal microbalance (EQCM), thiol chemistry was utilized to form the self‐assembled monolayer on EQCM electrode. Here, synergistic effects induced by various noncovalent interactions extended by multiple monomers (3‐sulfopropyl methacrylate potassium‐salt and benzyl methacrylate) were used in fabricating the imprinting polymeric matrix with additional firmness provided by N,N‐methylene‐bis‐acrylamide as cross‐linker and azo‐isobutyronitrile as initiator. Extraction of template molecule was carried out with phosphate buffer solution. After extraction of epitope molecules from the polymeric film, epitope molecularly imprinted polymeric films were fabricated on EQCM electrode surface. Nonimprinted polymers were also synthesized in the similar manner without epitope molecule. Detection limit of epitope molecularly imprinted polymers and imprinting factor (epitope molecularly imprinted polymers/nonimprinted polymers) was calculated 1.39 ng mL−1 and 12.27 respectively showing high binding capacity and specific recognition behavior toward template molecule. Simplicity of present method would put forward a fast, facile, cost‐effective diagnostic tool for mass health care.
3D phase contrast MRI in models of human airways: Validation of computational fluid dynamics simulations of steady inspiratory flow
Authors: Collier Guilhem J. , Kim Minsuok , Chung Yongmann , Wild Jim M.
Published: April 2018

Background

Knowledge of airflow patterns in the large airways is of interest in obstructive airways disease and in the development of inhaled therapies. Computational fluid dynamics (CFD) simulations are used to study airflow in realistic airway models but usually need experimental validation.

Purpose

To develop MRI‐based methods to study airway flow in realistic 3D‐printed models.

Study Type

Case control.

Phantom

Two 3D‐printed lung models.

Field Strength/Sequence

1.5–3T, flow MRI.

Assessment

Two human airway models, respectively including and excluding the oral cavity and upper airways derived from MR and CT imaging, were 3D‐printed. 3D flow MRI was performed at different flow conditions corresponding to slow and steady airflow inhalation rates. Water was used as the working fluid to mimic airflow. Dynamic acquisition of 1D velocity profiles was also performed at different locations in the trachea to observe variability during nonsteady conditions.

Statistical Tests

Linear regression analysis to compare both flow velocity fields and local flow rates from CFD simulations and experimental measurement with flow MRI.

Results

A good agreement was obtained between 3D velocity maps measured with flow MRI and predicted by CFD simulations, with linear regression R‐squared values ranging from 0.39 to 0.94 when performing a pixel‐by‐pixel comparison of each velocity component. The flow distribution inside the lung models was also similar, with average slope and R‐squared values of 0.96 and 0.99, respectively, when comparing local flow rates assessed at different branching locations. In the model including the upper airways, a turbulent laryngeal jet flow was observed with both methods and affected remarkably the velocity profiles in the trachea.

Data Conclusion

We propose flow MRI using water as a surrogate fluid to air, as a validation tool for CFD simulations of airflow in geometrically realistic models of the human airways.

Level of Evidence: 3

Technical Efficacy: Stage 2

J. Magn. Reson. Imaging 2018;47:1400–1409.
A 12‐year radar‐based climatology of daily and sub‐daily extreme precipitation over the Swiss Alps
Authors: Panziera L. , Gabella M. , Germann U. , Martius O.
Published: April 2018

The characterization of the alpine extreme precipitation is the basis to study the projected changes in frequency and intensity of heavy rainfall and is needed to improve the resilience of communities to high‐impact weather. Climatological features of extreme daily and sub‐daily precipitation are documented here for the Swiss Alps and surrounding regions at a high spatial resolution (1 km2). The basis is 12 years of data from rain gauges and CombiPrecip, a rainfall field produced by locally adjusting the radar precipitation map to the values measured by rain gauges. The agreement between rain gauges and CombiPrecip concerning both the timing and the magnitude of the extreme events is quantified by cross‐validation; overall, it increases with diminishing the severity of the extremes and increasing accumulation time. If the extremes represent on average the 10 most intense rainfall accumulations per year, in general 50–65% of rain gauges extremes are extremes also for CombiPrecip, 40–50% of CombiPrecip extremes are not extremes according to rain gauges, and CombiPrecip extremes are till 7% lower than rain gauges extremes. The maps presented in this paper show that both daily and sub‐daily extremes are more intense along the alpine slopes compared to the crest of the Alps in all seasons, with the Lago Maggiore region showing the largest values. The fraction of yearly rainfall due to extremes is generally smaller in the Alps than in flat terrain. Extreme 1‐hr precipitation is more clustered in time in the inner Alps, but is less frequent, and exhibits a strong diurnal cycle in summer. The paper also shows that sub‐daily and daily extremes occur essentially over the same 24‐hr period.
Stress‐Generative Effects of Posttraumatic Stress Disorder: Transactional Associations Between Posttraumatic Stress Disorder and Stressful Life Events in a Longitudinal Sample
Authors: Maniates Hannah , Stoop Tawni B. , Miller Mark W. , Halberstadt Lisa , Wolf Erika J.
Published: April 2018

Longitudinal studies have demonstrated transactional associations between psychopathology and stressful life events (SLEs), such that psychopathology predicts the occurrence of new SLEs, and SLEs in turn predict increasing symptom severity. The association between posttraumatic stress disorder (PTSD), specifically, and stress generation remains unclear. This study used temporally sequenced data from 116 veterans (87.9% male) to examine whether PTSD symptoms predicted new onset SLEs, and if these SLEs were associated with subsequent PTSD severity. The SLEs were objectively rated, using a clinician‐administered interview and consensus‐rating approach, to assess the severity, frequency, and personal dependence (i.e., if the event was due to factors that were independent of or dependent on the individual) of new‐onset SLEs. A series of mediation models were tested, and results provided evidence for moderated mediation whereby baseline PTSD severity robustly predicted personally dependent SLEs, B = 0.03, p = .006, and dependent SLEs predicted increases in follow‐up PTSD symptom severity, B = −0.04, p = .003, among participants with relatively lower baseline PTSD severity. After we controlled for baseline PTSD severity, personality traits marked by low constraint (i.e., high impulsivity) were also associated with an increased number of dependent SLEs. Our results provide evidence for a stress‐generative role of PTSD and highlight the importance of developing interventions aimed at reducing the occurrence of personally dependent stressors.
Numerical prediction of gas migration properties in Callovo‐Oxfordian (COx) argillite using morpho‐mathematical operations
Authors: Zhang Xiang , Duveau Gilles , Colliat Jean‐Baptiste
Published: April 2018

The feasibility study of long‐term radioactive waste storage in low‐permeable rocks has been performed by considering various damage and failure scenarios. This study aims at the numerical investigation of gas (mainly produced by corrosion of metallic parts) migration properties through the low‐permeable formation of Callovo‐Oxfordian argillite. Traditional methods, based on macroscopic approaches or homogeneous transport properties, are inappropriate to analyze this issue at the mesoscopic/microscopic scale. In this study, realistic porous space morphologies are constructed through union of excursions of random fields considering different experimental pore size distributions. Afterwards, purely geometric analysis of pore space is conducted by morpho‐mathematical operations for the purpose of the extraction of preferential gas transport pathways and the prediction of the gas entry pressure, the gas breakthrough pressure, and the following imbibition process.
Steady‐state diffusion approximations for discrete‐time queue in hospital inpatient flow management
Authors: Feng Jiekun , Shi Pengyi
Published: April 2018

In this article, we analyze a discrete‐time queue that is motivated from studying hospital inpatient flow management, where the customer count process captures the midnight inpatient census. The stationary distribution of the customer count has no explicit form and is difficult to compute in certain parameter regimes. Using the Stein's method framework, we identify a continuous random variable to approximate the steady‐state customer count. The continuous random variable corresponds to the stationary distribution of a diffusion process with state‐dependent diffusion coefficients. We characterize the error bounds of this approximation under a variety of system load conditions—from lightly loaded to heavily loaded. We also identify the critical role that the service rate plays in the convergence rate of the error bounds. We perform extensive numerical experiments to support the theoretical findings and to demonstrate the approximation quality. In particular, we show that our approximation performs better than those based on constant diffusion coefficients when the number of servers is small, which is relevant to decision making in a single hospital ward.