bluuebunny/crossref_metadata_2025 huggingface dataset:
Transcriptional elongation factor Paf1 core complex adopts a spirally wrapped solenoidal topology
Authors: Deng Pujuan , Zhou Yuqiao , Jiang Junyi , Li Haojie , Tian Wei , Cao Yinghua , Qin Yan , Kim Jaehoon , Roeder Robert G. , Patel Dinshaw J. , Wang Zhanxin
Published: September 2018

The polymerase-associated factor 1 (Paf1) complex is a general transcription elongation factor of RNA polymerase II, which is composed of five core subunits, Paf1, Ctr9, Cdc73, Leo1, and Rtf1, and functions as a diverse platform that broadly affects gene expression genome-wide. In this study, we solved the 2.9-Å crystal structure of the core region composed of the Ctr9-Paf1-Cdc73 ternary complex from a thermophilic fungi, which provides a structural perspective of the molecular details of the organization and interactions involving the Paf1 subunits in the core complex. We find that Ctr9 is composed of 21 tetratricopeptide repeat (TPR) motifs that wrap three circular turns in a right-handed superhelical manner around the N-terminal region of an elongated single-polypeptide–chain scaffold of Paf1. The Cdc73 fragment is positioned within the surface groove of Ctr9, where it contacts mainly with Ctr9 and minimally with Paf1. We also identified that the Paf1 complex preferentially binds single-strand–containing DNAs. Our work provides structural insights into the overall architecture of the Paf1 complex and paves the road forward for understanding the molecular mechanisms of the Paf1 complex in transcriptional regulation.
Fibroblasts lacking nuclear lamins do not have nuclear blebs or protrusions but nevertheless have frequent nuclear membrane ruptures
Authors: Chen Natalie Y. , Kim Paul , Weston Thomas A. , Edillo Lovelyn , Tu Yiping , Fong Loren G. , Young Stephen G.
Published: September 2018

Significance

Genetic defects in nuclear lamins or reduced expression of nuclear lamins is accompanied by nuclear blebs and an increased susceptibility for nuclear membrane ruptures. Nuclear membrane ruptures are exacerbated by subjecting cells to mechanical forces. Here, we demonstrate that cells lacking nuclear lamins have oblong nuclei, but no nuclear blebs and no protrusions of the chromatin beyond the bounds of the nuclear membranes. Nevertheless, the cells displayed frequent and prolonged nuclear membrane ruptures, associated with DNA damage and occasionally by cell death. Thus, the nuclear lamina is crucial for the integrity of the nuclear membranes and for limiting damage to DNA. We suspect that our observations could be relevant to disease caused by defects or deficiencies in the nuclear lamins.
Gender variation in signs of sexual behaviour in Hong Kong Sign Language
Authors: Wei Monica X. , Sze Felix Y. B. , Wong Aaron Y. L.
Published: September 2018

This paper discusses possible gender variation in the signs of sexual behaviour in Hong Kong Sign Language (HKSL). The data comes
from a research project that aims at documenting and analyzing sex-related signs in this sign language for the sake of producing
materials for sex education and interpreter training programs. Since sex is a highly taboo topic, euphemistic signs for the target
concepts were collected and analyzed. This paper presents evidence that linguistic variation of neutral and euphemistic
expressions of sex-related concepts exists in HKSL, and that gender plays a role in the choice of some but not all variants and
their euphemistic counterparts.
Tracing the evolutionary trajectory of verbal working memory with neuro-archaeology
Authors: Putt Shelby S. , Wijeakumar Sobanawartiny
Published: September 2018

We used optical neuroimaging to explore the extent of functional overlap between working memory (WM) networks involved in language and Early Stone Age toolmaking behaviors. Oldowan tool production activates two verbal WM areas, but the functions of these areas are indistinguishable from general auditory WM, suggesting that the first hominin toolmakers relied on early precursors of verbal WM to make simple flake tools. Early Acheulian toolmaking elicits activity in a region bordering on Broca’s area that is involved in both visual and verbal WM tasks. The sensorimotor and mirror neurons in this area, along with enhancement of general WM capabilities around 1.8 million years ago, may have provided the scaffolding upon which a WM network dedicated to processing exclusively linguistic information could evolve. In the road map going forward, neuro-archaeologists should investigate the trajectory of WM over the course of human evolution to better understand its contribution to language origins.
From actions to events
Authors: Pustejovsky James
Published: September 2018

In this paper, I argue that an important component of the language-ready brain is the ability to recognize and conceptualize events. By ‘event’, I mean any situation or activity in the world or our mental life, that we find salient enough to individuate as a thought or word. While this may sound either trivial or non-unique to humans, I hope to show that abstracting away events and their participants from the embodied flow of experience is a characteristic unique to humans. This ability is enabled, I will argue, by two critical competencies that act as scaffolds for language-ready thought in the prehuman brain. The first, as argued by Arbib (2006,2012,2016) and others, is a sophisticated system of gesture production and understanding in prehumans, which provided a template for schema-like sequencing and slot-filling of information units. The second involves the integration of multiple modalities of expression in the communicative act, in particular, the alignment of co-gestural speech and co-speech gesture. With such computational facilities, action-based gestures can be abstracted away from their associated objects and become full event representations. This view supports the MSH argument for the emergence of more complex linguistic expressions from initially holophrastic units. In particular, actions can be thought of as protoverbs, which through this process are abstracted to full event descriptions, i.e., verbs.
Introducing a special issue
Authors: Arbib Michael A.
Published: September 2018

The paper introduces a Special Issue of Interaction Studies which includes 21 papers based on presentations and discussion
at a workshop entitled “How the Brain Got Language: Towards a New Road Map.” Unifying themes include the comparative study of brain,
behavior and communication in monkeys, apes and humans, and an EvoDevoSocio framework for approaching biological and cultural evolution
within a shared perspective. The final article of the special issue builds on the previous papers to present “The Comparative
Neuroprimatology 2018 (CNP-2018) Road Map for Research on How the Brain Got Language.”
STatistical Inference Relief (STIR) feature selection
Authors: Le Trang T , Urbanowicz Ryan J , Moore Jason H , McKinney Brett A
Published: September 2018

Motivation

Relief is a family of machine learning algorithms that uses nearest-neighbors to select features whose association with an outcome may be due to epistasis or statistical interactions with other features in high-dimensional data. Relief-based estimators are non-parametric in the statistical sense that they do not have a parameterized model with an underlying probability distribution for the estimator, making it difficult to determine the statistical significance of Relief-based attribute estimates. Thus, a statistical inferential formalism is needed to avoid imposing arbitrary thresholds to select the most important features. We reconceptualize the Relief-based feature selection algorithm to create a new family of STatistical Inference Relief (STIR) estimators that retains the ability to identify interactions while incorporating sample variance of the nearest neighbor distances into the attribute importance estimation. This variance permits the calculation of statistical significance of features and adjustment for multiple testing of Relief-based scores. Specifically, we develop a pseudo t-test version of Relief-based algorithms for case-control data.

Results

We demonstrate the statistical power and control of type I error of the STIR family of feature selection methods on a panel of simulated data that exhibits properties reflected in real gene expression data, including main effects and network interaction effects. We compare the performance of STIR when the adaptive radius method is used as the nearest neighbor constructor with STIR when the fixed-k nearest neighbor constructor is used. We apply STIR to real RNA-Seq data from a study of major depressive disorder and discuss STIR’s straightforward extension to genome-wide association studies.

Availability and implementation

Code and data available at http://insilico.utulsa.edu/software/STIR.

Supplementary information

Supplementary data are available at Bioinformatics online.
Contemporaneous and Granger causality among US corn cash and futures prices
Authors: Xu Xiaojie
Published: September 2018

This paper examines contemporaneous and Granger causality among US corn futures and seven cash prices from major producing states for January 2006–March 2011. Causal flows from futures to cash prices are identified with contemporaneous and in-sample Granger causality tests but not with the out-of-sample Granger causality test. While no interstate in-sample or out-of-sample Granger causality is found, contemporaneous causal linkages are revealed. No causality from cash to futures prices is determined.
Epigenetic changes in preterm birth placenta suggest a role for ADAMTS genes in spontaneous preterm birth
Authors: Mani Sneha , Ghosh Jayashri , Lan Yemin , Senapati Suneeta , Ord Teri , Sapienza Carmen , Coutifaris Christos , Mainigi Monica
Published: September 2018

Preterm birth (PTB) affects approximately 1 in 10 pregnancies and contributes to approximately 50% of neonatal mortality. However, despite decades of research, little is understood about the etiology of PTB, likely due to the multifactorial nature of the disease. In this study, we examined preterm and term placentas, from unassisted conceptions and those conceived using in vitro fertilization (IVF). IVF increases the risk of PTB and causes epigenetic change in the placenta and fetus; therefore, we utilized these patients as a unique population with a potential common etiology. We investigated genome-wide DNA methylation in placentas from term IVF, preterm IVF, term control (unassisted conception) and preterm control pregnancies and discovered epigenetic dysregulation of multiple genes involved in cell migration, including members of the ADAMTS family, ADAMTS12 and ADAMTS16. These genes function in extracellular matrix regulation and tumor cell invasion, processes replicated by invasive trophoblasts (extravillous trophoblasts (EVTs)) during early placentation. Though expression was similar between term and preterm placentas, we found that both genes demonstrate high expression in first- and second-trimester placenta, specifically in EVTs and syncytiotrophoblasts. When we knocked down ADAMTS12 or ADAMTS16in vitro, there was poor EVT invasion and reduced matrix metalloproteinase activity, reinforcing their critical role in placentation. In conclusion, utilizing a population at high risk for PTB, we have identified a role for ADAMTS gene methylation in regulating early placentation and susceptibility to PTB.
GLS hyperactivity causes glutamate excess, infantile cataract and profound developmental delay
Authors: Rumping Lynne , Tessadori Federico , Pouwels Petra J W , Vringer Esmee , Wijnen Jannie P , Bhogal Alex A , Savelberg Sanne M C , Duran Karen J , Bakkers Mark J G , Ramos Rúben J J , Schellekens Peter A W , Kroes Hester Y , Klomp Dennis W J , Black Graeme C M , Taylor Rachel L , Bakkers Jeroen P W , Prinsen Hubertus C M T , van der Knaap Marjo S , Dansen Tobias B , Rehmann Holger , Zwartkruis Fried J T , Houwen Roderick H J , van Haaften Gijs , Verhoeven-Duif Nanda M , Jans Judith J M , van Hasselt Peter M
Published: September 2018

Loss-of-function mutations in glutaminase (GLS), the enzyme converting glutamine into glutamate, and the counteracting enzyme glutamine synthetase (GS) cause disturbed glutamate homeostasis and severe neonatal encephalopathy. We report a de novo Ser482Cys gain-of-function variant in GLS encoding GLS associated with profound developmental delay and infantile cataract. Functional analysis demonstrated that this variant causes hyperactivity and compensatory downregulation of GLS expression combined with upregulation of the counteracting enzyme GS, supporting pathogenicity. Ser482Cys-GLS likely improves the electrostatic environment of the GLS catalytic site, thereby intrinsically inducing hyperactivity. Alignment of +/−12.000 GLS protein sequences from >1000 genera revealed extreme conservation of Ser482 to the same degree as catalytic residues. Together with the hyperactivity, this indicates that Ser482 is evolutionarily preserved to achieve optimal—but submaximal—GLS activity. In line with GLS hyperactivity, increased glutamate and decreased glutamine concentrations were measured in urine and fibroblasts. In the brain (both grey and white matter), glutamate was also extremely high and glutamine was almost undetectable, demonstrated with magnetic resonance spectroscopic imaging at clinical field strength and subsequently supported at ultra-high field strength. Considering the neurotoxicity of glutamate when present in excess, the strikingly high glutamate concentrations measured in the brain provide an explanation for the developmental delay. Cataract, a known consequence of oxidative stress, was evoked in zebrafish expressing the hypermorphic Ser482Cys-GLS and could be alleviated by inhibition of GLS. The capacity to detoxify reactive oxygen species was reduced upon Ser482Cys-GLS expression, providing an explanation for cataract formation. In conclusion, we describe an inborn error of glutamate metabolism caused by a GLS hyperactivity variant, illustrating the importance of balanced GLS activity.
Development and Validation of a Risk Score for Febrile Neutropenia After Chemotherapy in Patients With Cancer: The FENCE Score
Authors: Aagaard Theis , Roen Ashley , Reekie Joanne , Daugaard Gedske , Brown Peter de Nully , Specht Lena , Sengeløv Henrik , Mocroft Amanda , Lundgren Jens , Helleberg Marie
Published: September 2018

Background

Febrile neutropenia (FN) after chemotherapy causes a high burden of morbidity and mortality. We aimed to develop and validate a risk score to predict FN in the first cycle of chemotherapy.

Methods

We included patients with solid cancers and diffuse large B-cell lymphomas at Rigshospitalet, University of Copenhagen, 2010-2016. Predictors of FN were analyzed using Poisson regression and random split-sampling.

Results

Among 6294 patients in the derivation cohort, 360 developed FN. Female sex, older age, cancer type, disease stage, low albumin, elevated bilirubin, low creatinine clearance, infection before chemotherapy, and number of and type of chemotherapy drugs predicted FN. Compared with those at low risk (n = 2520, 40.0%), the incidence rate ratio of developing FN was 4.8 (95% confidence interval [CI] = 2.9 to 8.1), 8.7 (95% CI = 5.3 to 14.1) and 24.0 (95% CI = 15.2 to 38.0) in the intermediate (n = 1294, 20.6%), high (n = 1249, 19.8%) and very high (n = 1231, 19.6%) risk groups, respectively, corresponding to a number needed to treat with granulocyte colony-stimulating factors to avoid one FN event in the first cycle of 284, 60, 34 and 14. The discriminatory ability (Harrell’s C-statistic = 0.80, 95% CI = 0.78 to 0.82) was similar in the validation cohort (n = 3163) (0.79, 95% CI = 0.75 to 0.82).

Conclusion

We developed and internally validated a risk score for FN in the first cycle of chemotherapy. The FENCE score is available online and provides good differentiation of risk groups.
Evaluation of Intravenous Posaconazole Dosing and Pharmacokinetic Target Attainment in Pediatric Patients
Authors: Nickless Jenna R , Bridger Kathryn E , Vora Surabhi B , Brothers Adam W
Published: September 2018

Limited data exist on intravenous (IV) posaconazole dosing and the risk for hepatotoxicity it confers to children. In this study, we evaluated dosing and resulting trough levels in 10 pediatric patients on IV posaconazole. A therapeutic level in these patients was achieved 95% of the time. We found a median minimum effective dose of 6.55 mg/kg of body weight. No correlation was found between the duration or posaconazole trough level and an increased alanine transaminase level.
SDSS J0909+4449: A large-separation strongly lensed quasar at z ∼ 2.8 with three images
Authors: Shu Yiping , Marques-Chaves Rui , Evans N Wyn , Pérez-Fournon Ismael
Published: September 2018

We report the discovery of SDSS J0909+4449, an exceptional system consisting of a quasar at z = 2.788 strongly lensed by a group of galaxies at z ∼ 0.9 into three images separated by up to 14 arcsec based on archival data collected by the Sloan Digital Sky Survey, extended Baryon Oscillation Spectroscopic Survey, Beijing–Arizona Sky Survey, the Mayall z-band Legacy Survey, and the Gemini Telescope. We discuss two hypotheses on the nature of SDSS J0909+4449, i.e. a rare triply imaged quasar in the naked cusp configuration and a typical quadruply imaged quasar with the fourth image undetected in this data. We find that simple lens models can provide excellent fits to the observed image positions and the non-detection under either hypothesis. Deeper imaging data, spectroscopic observations, and follow-up light-curve measurements will be helpful in determining which hypothesis is correct and provide better constraints on the lens mass distribution. Nevertheless, given its unusually large image separations, SDSS J0909+4449 will be a unique probe for the mass structure and the underlying cooling and stellar feedback processes on group or cluster scales.
Health and mass unemployment events—developing a framework for preparedness and response
Authors: Davies A R , Homolova L , Grey C N B , Bellis M A
Published: September 2018

Background

Mass unemployment events are not uncommon yet the impact on health is not well recognised. There is a need for a preparedness and response framework, as exists for other events that threaten population health.

Methods

Framework informed by a narrative review of the impact of mass unemployment on health (studies published in English from 1990 to 2016), and qualitative data from 23 semi-structured interviews with individuals connected to historical national and international events, addressing gaps in published literature on lessons learnt from past responses.

Results

Economic and employment shock triggered by mass unemployment events have a detrimental impact on workers, families and communities. We present a public health informed response framework which includes (i) identify areas at risk, (ii) develop an early warning system, (iii) mobilise multi-sector action including health and community, (iv) provision of support across employment, finance and health (v) proportionate to need, (vi) extend support to family members and (vii) communities and (viii) evaluate and learn.

Conclusion

Mass unemployment events have an adverse impact on the health, financial and social circumstances of workers, families, and communities. This is the first framework for action to mitigate and address the detrimental impact of mass unemployment events on population health.
Education Spillovers in Farm Productivity: Revisiting the Evidence
Authors: Gille Véronique
Published: September 2018

This paper exploits the social organization of India to revisit the question of education spillovers in farm productivity. The fact that social interactions mainly occur within castes in rural India provides tools to show that the observed correlation between farm productivity and neighbors’ education is likely to be a spillover effect. In particular, there are no cross-caste and no cross-occupation effects, which underlines that, under specific assumptions, which are stated and explored in the paper, the education of neighbors does not capture the effect of group unobservables. This evidence is complemented by separate estimations by crops, which show results that are consistent with education spillovers. The strategy used in this paper helps understand and interpret previous findings from the literature.
A survey on polynomial in momenta integrals for billiard problems
Authors: Bialy Misha , Mironov Andrey E.
Published: September 2018

In this paper, we give a short survey of recent results on the algebraic version of the Birkhoff conjecture for integrable billiards on surfaces of constant curvature. We also discuss integrable magnetic billiards. As a new application of the algebraic technique, we study the existence of polynomial integrals for the two-sided magnetic billiards introduced by Kozlov and Polikarpov.

This article is part of the theme issue ‘Finite dimensional integrable systems: new trends and methods’.
Asymptotic velocity for four celestial bodies
Authors: Knauf Andreas
Published: September 2018

Asymptotic velocity is defined as the Cesàro limit of velocity. As such, its existence has been proved for bounded interaction potentials. This is known to be wrong in celestial mechanics with four or more bodies. Here, we show for a class of pair potentials including the homogeneous ones of degree −
α
for
α
∈(0, 2), that asymptotic velocities exist for up to four bodies, dimension three or larger, for any energy and
almost all
initial conditions on the energy surface.

This article is part of the theme issue ‘Finite dimensional integrable systems: new trends and methods’.
The
U
(
n
) Gelfand–Zeitlin system as a tropical limit of Ginzburg–Weinstein diffeomorphisms
Authors: Alekseev A. , Lane J. , Li Y.
Published: September 2018

In this paper, we show that the Ginzburg–Weinstein diffeomorphism

of Alekseev & Meinrenken (Alekseev, Meinrenken 2007
J. Differential Geom.
76
, 1–34. (10.4310/jdg/1180135664)) admits a scaling tropical limit on an open dense subset of

. The target of the limit map is a product

, where

is the interior of a cone,
T
is a torus, and

carries an integrable system with natural action-angle coordinates. The pull-back of these coordinates to

recovers the Gelfand–Zeitlin integrable system of Guillemin & Sternberg (Guillemin, Sternberg 1983
J. Funct. Anal.
52
, 106–128. (10.1016/0022-1236(83)90092-7)). As a by-product of our proof, we show that the Lagrangian tori of the Flaschka–Ratiu integrable system on the set of upper triangular matrices meet the set of totally positive matrices for sufficiently large action coordinates.

This article is part of the theme issue ‘Finite dimensional integrable systems: new trends and methods’.
Coupled single-cell CRISPR screening and epigenomic profiling reveals causal gene regulatory networks
Authors: Rubin Adam J. , Parker Kevin R. , Satpathy Ansuman T. , Qi Yanyan , Wu Beijing , Ong Alvin J. , Mumbach Maxwell R. , Ji Andrew L. , Kim Daniel S. , Cho Seung Woo , Zarnegar Brian J. , Greenleaf William J. , Chang Howard Y. , Khavari Paul A.
Published: September 2018

Here we present Perturb-ATAC, a method which combines multiplexed CRISPR interference or knockout with genome-wide chromatin accessibility profiling in single cells, based on the simultaneous detection of CRISPR guide RNAs and open chromatin sites by assay of transposase-accessible chromatin with sequencing (ATAC-seq). We applied Perturb-ATAC to transcription factors (TFs), chromatin-modifying factors, and noncoding RNAs (ncRNAs) in ∼4,300 single cells, encompassing more than 63 unique genotype-phenotype relationships. Perturb-ATAC in human B lymphocytes uncovered regulators of chromatin accessibility, TF occupancy, and nucleosome positioning, and identified a hierarchical organization of TFs that govern B cell state, variation, and disease-associatedcis-regulatory elements. Perturb-ATAC in primary human epidermal cells revealed three sequential modules ofcis-elements that specify keratinocyte fate, orchestrated by the TFs JUNB, KLF4, ZNF750, CEBPA, and EHF. Combinatorial deletion of all pairs of these TFs uncovered their epistatic relationships and highlighted genomic co-localization as a basis for synergistic interactions. Thus, Perturb-ATAC is a powerful and general strategy to dissect gene regulatory networks in development and disease.

Highlights

A new method for simultaneous measurement of CRISPR perturbations and chromatin state in single cells.

Perturb-ATAC reveals regulatory factors that controlcis-element accessibility,trans-factor occupancy, and nucleosome positioning.

Perturb-ATAC reveals regulatory modules of coordinatedtrans-factor activity in B lymphoblasts.

Keratinocyte differentiation is orchestrated by synergistic activities of co-binding TFs oncis-elements.
Symbiosis, Selection and Novelty: Freshwater Adaptation in the Unique Sponges of Lake Baikal
Authors: Kenny Nathan J , Plese Bruna , Riesgo Ana , Itskovich Valeria B.
Published: September 2018

Freshwater sponges (Spongillida) are a unique lineage of demosponges that secondarily colonized lakes and rivers and are now found ubiquitously in these ecosystems. They developed specific adaptations to freshwater systems, including the ability to survive extreme thermal ranges, long-lasting dessication, anoxia, and resistance to a variety of pollutants. While spongillids have colonized all freshwater systems, the family Lubomirskiidae is endemic to Lake Baikal, and plays a range of key roles in this ecosystem. Our work compares the genomic content and microbiome of individuals of three species of the Lubomirskiidae, providing hypotheses for how molecular evolution has allowed them to adapt to their unique environments. We have sequenced deep (>92% of the metazoan ‘Benchmarking Universal Single-Copy Orthologs’ (BUSCO) set) transcriptomes from three species of Lubomirskiidae and a draft genome resource forLubomirskia baikalensis. We note Baikal sponges contain unicellular algal and bacterial symbionts, as well as the dinoflagellateGyrodinium. We investigated molecular evolution, gene duplication and novelty in freshwater sponges compared to marine lineages. Sixty one orthogroups have consilient evidence of positive selection. Transporters (e.g.zinc transporter-2),transcription factors (aristaless-related homeobox) and structural proteins (for exampleactin-3), alongside other genes, are under strong evolutionary pressure in freshwater, with duplication driving novelty across the Spongillida, but especially in the Lubomirskiidae. This addition to knowledge of freshwater sponge genetics provides a range of tools for understanding the molecular biology and, in the future, the ecology (for example, colonization and migration patterns) of these key species.
Improved real-time influenza surveillance using Internet search data in eight Latin American countries
Authors: Clemente Leonardo , Lu Fred , Santillana Mauricio
Published: September 2018

A real-time methodology for monitoring flu activity in middle income countries that is simultaneously accurate and generalizable has not yet been presented. We demonstrate here that a self-correcting machine learning method leveraging Internet-based search activity produces reliable and timely flu estimates in multiple Latin American countries.
ProgressiveMycobacterium abscessuslung infection in C3HeB/FeJ mice associated with corticosteroid administration
Authors: Maggioncalda Emily C. , Story-Roller Elizabeth , Ammerman Nicole C. , Nuermberger Eric L. , Lamichhane Gyanu
Published: September 2018

Mycobacterium abscessus(Mab) is a rapidly-growing nontuberculous mycobacterium that is a growing health concern among both immunocompetent and immunocompromised patient populations. It most commonly causes skin and soft tissue or pulmonary infection. As an emerging health issue there is much that still needs to be understood about the infection and its progression to disease. In the context of pulmonary infection, anin vivosystem ofMabinfection that permits investigation of host-microbe interactions that result inMabinfection and the transition to pathogenesis, and also the evaluation of treatments, is an essential tool that is currently lacking. Here, we describe a system of pulmonaryMabinfection in the C3HeB/FeJ mouse strain under corticosteroid immunosuppressive therapy that progresses to pathology.
High-throughput identification of dominant negative polypeptides in yeast
Authors: Dorrity Michael W. , Queitsch Christine , Fields Stanley
Published: September 2018

Dominant negative polypeptides can act as inhibitors by binding to the wild type protein or by titrating an essential ligand. Here, we use high-throughput sequencing of DNA libraries composed of fragments of yeast genes to identify dominant negative polypeptides based on their depletion during cell growth. The method uncovers numerous inhibitory polypeptides for a protein and thus is capable of defining interacting domains with exquisite resolution, even pinpointing individual residues that contact ligands.
A human embryonic stem cell model of Aβ-dependent chronic progressive neurodegeneration
Authors: Ubina Teresa , Magallanes Martha , Srivastava Saumya , Warden Charles , Yee Jiing-Kuan , Salvaterra Paul M.
Published: September 2018

We describe construction and phenotypic analysis of a human embryonic stem cell model of progressive Aβ-dependent neurodegeneration (ND) with potential relevance to Alzheimer’s disease (AD). We modified one allele of the normal APP locus to directly express a secretory form of Aβ40 or Aβ42, eliminating the need for amyloidogenic APP proteolysis. Following neuronal differentiation edited cell lines specifically accumulate aggregated/oligomeric Aβ, exhibit a synaptic deficit and have an abnormal accumulation of endolysosomal vesicles. Edited cultures progress to a stage of overt ND. All phenotypes appear at earlier culture times for Aβ42 relative to Aβ40. Whole transcriptome RNA-Seq analysis identified 23 up and 70 down regulated genes (DEGs) with similar directional fold change but larger absolute values in the Aβ42 samples suggesting common underlying pathogenic mechanisms. Pathway/annotation analysis suggested that down regulation of extracellular matrix and cilia functions are significantly overrepresented. This cellular model could be useful for uncovering mechanisms directly linking Aβ to neuronal death and as a tool to screen for new therapeutic agents that slow or prevent human ND.
Individual response to mTOR inhibition in delaying replicative senescence of mesenchymal stromal cells
Authors: Antonioli Eliane , Torres Natália , Ferretti Mario , Piccinato Carla A. , Sertie Andrea L.
Published: September 2018

Background aims

Delaying replicative senescence and extending lifespan of human mesenchymal stromal cells (MSCs) may enhance their potential for tissue engineering and cell based therapies. Accumulating evidence suggests that inhibitors of the mTOR signaling pathway, such as rapamycin, constitute promising pharmacological agents to retard senescence and extend stemness properties of various progenitor cell types. Here, we investigated whether the ability of rapamycin to postpone replicative senescence varies among bone marrow MSC samples (BM-MSCs) derived from different healthy donors, and explored the molecular mechanisms that drive rapamycin-mediated lifespan increment.

Methods

BM-MSCs at early passages were serially passaged either in absence or continuous presence of rapamycin and the number of cell population doublings until growth arrest was measured. The inhibition of mTOR signaling was assessed by the phosphorylation status of the downstream target RPS6. The expression levels of several senescence and pluripotency markers at early and late/senescent passages were analyzed by RT-qPCR, flow cytometry and western blot.

Results

We found that the lifespan extension in response to the continuous rapamycin treatment was highly variable among samples, but effective in most BM-MSCs. Despite all rapamycin-treated cells secreted significantly reduced levels of IL6, a major SASP cytokine, and expressed significantly higher levels of the pluripotency marker NANOG, the expression patterns of these markers were not correlated with the rapamycin-mediated increase in lifespan. Interestingly, rapamycin-mediated life-span extension was significantly associated only with repression of p16INK4A protein accumulation.

Conclusions

Taken together, our results suggest that some, but not all, BM-MSC samples would benefit from using rapamycin to postpone replicative arrest and reinforce a critical role of p16INK4A protein downregulation in this process.
Spatial patterns of species richness and nestedness in ant assemblages along an elevational gradient in a Mediterranean mountain range
Authors: Flores O. , Seoane J. , Hevia V. , Azcárate F.M.
Published: September 2018

The study of biodiversity spatial patterns along ecological gradients can serve to elucidate factors shaping biological community structure and predict ecosystem responses to global change. Ant assemblages are particularly interesting as study cases, because ant species play a key role in many ecosystem processes and have frequently been identified as useful bioindicators. Here we analyzed the response of ant species richness and assemblage composition to elevational gradients in Mediterranean grasslands and subsequently tested whether these responses were stable spatially and temporally. We sampled ant assemblages in two years (2014, 2015) in two mountain ranges (Guadarrama, Serrota) in Central Spain, along an elevational gradient ranging from 685 to 2390 m a.s.l.

Jackknife estimates of ant species richness ranged from three to 18.5 species and exhibited a hump-shaped relationship with elevation that peaked at mid range values (1100 - 1400 m). This pattern was transferable temporally and spatially. Elevation was significantly related to ant assemblage composition and facilitated separation of higher elevation assemblages (> 1700 m) from the remaining lower elevation species groups. Ant assemblages were nested; therefore species assemblages with a decreased number of species were a subset of the richer assemblages, although species turnover was more important than pure nestedness in all surveys. The degree of nestedness changed non-linearly as a cubic polynomial with elevation. These assembly patterns were observed over time but not between the two study regions.

We concluded double environmental stressors typical of Mediterranean mountains explained species richness patterns: drought at low elevations and cold temperatures at high elevations likely constrained richness at both extremes of elevational gradients. The fact that species turnover showed a dominant role over pure nestedness suggested current ant assemblages were context-dependent (spatio-temporal factors) and highly vulnerable to global change, which threatens the conservation of present day native ant communities, particularly at high elevations.
First sexual experiences determine the development of conditioned ejaculatory preference in male rats
Authors: Quintana Gonzalo R. , Guizar Andrés , Rassi Sarah , Pfaus James G.
Published: September 2018

We have shown previously that male rats develop a conditioned ejaculatory preference (CEP) for females scented with a neutral odor like almond or lemon that is paired with the male's post-ejaculatory reward state during their first and subsequent early sexual experiences. However, preexposing males to the neutral odor alone prior to its pairing with sexual reward results in latent inhibition. Here, we examined the phenomenon of unconditioned stimulus (US) preexposure, in which male rats were preexposed to the ejaculatory reward state either one or five times with scented (ScF) versus unscented (UnScF) females prior to multiple ejaculatory trials with females in the opposite condition (e.g., ScF preexposure received 10 subsequent ejaculatory trials with UnScF, whereas UnScF preexposure received 10 subsequent ejaculatory trials with ScF). As before, mate and partner preference was evaluated in an open field where each male had access to two females, one ScF and the other UnScF. Males that underwent five trials of preexposure did not display a CEP for either female. Conversely, males preexposed once to a ScF, and later trained with UnScF developed a preference for the latter, whereas males preexposed once to the UnScF, and then trained with ScF did not show a preference for any of the females. Subsequent exposure to the odor cue alone revealed different patterns of brain activation in areas related to sexual behavior that depended on the animal's group membership. Altogether, these findings demonstrate the pivotal role of first sexual experiences in the establishment of future sexual partner preference in the male rat, and suggest an innate preference for estrous odors over neutral odors that can become conditioned subsequently as predictors of sexual reward.
Tubular linear permanent magnet synchronous machine applied to semi-active suspension systems
Authors: Zanatta Ana Paula , Bandeira Boff Ben Hur , Eckert Paulo Roberto , Ferreira Flores Filho Aly , Dorrell David George
Published: September 2018

Purpose

Semi-active suspension systems with electromagnetic dampers allow energy regeneration and the required control strategies are easier to implement than the active suspensions are. This paper aims to address the application of a tubular linear permanent magnet synchronous machine for a semi-active suspension system.

Design/methodology/approach

Classical rules of mechanics and electromagnetics were applied to describe a dynamic model combining vibration and electrical machines theories. A multifaceted MATLAB®/Simulink model was implemented to incorporate equations and simulate global performance. Experimental tests on an actual prototype were carried out to investigate displacement transmissibility of the passive case. In addition, simulation results were shown for the dissipative semi-active case.

Findings

The application of the developed model suggests convergent results. For the passive case, numerical and experimental outcomes validate the parameters and confirm system function and proposed methodology. MATLAB®/Simulink results for the semi-active case are consistent, showing an improvement on the displacement transmissibility. These agree with the initial conceptual thoughts.

Originality/value

The use of linear electromagnetic devices in suspension systems is not a novel idea. However, most published papers on this subject outline active solutions, neglect semi-active ones and focus on experimental studies. However, here a dynamic mechanical-electromagnetic coupled model for a semi-active suspension system is reported. This is in conjunction with a linear electromagnetic damper.
A multi-objective supplier selection model for green supply chain network under uncertainty
Authors: Khalilzadeh Mohammad , Derikvand Hadis
Published: September 2018

Purpose

Globalization of markets and pace of technological change have caused the growing importance of paying attention to supplier selection problem. Therefore, this study aims to choose the best suppliers by providing a mathematical model for the supplier selection problem considering the green factors and stochastic parameters. This paper aims to propose a multi-objective model to identify optimal suppliers for a green supply chain network under uncertainty.

Design/methodology/approach

The objective of this model is to select suppliers considering total cost, total quality parts and total greenhouse gas emissions. Also, uncertainty is tackled by stochastic programming, and the multi-objective model is solved as a single-objective model by the LP-metric method.

Findings

Twelve numerical examples are provided, and a sensitivity analysis is conducted to demonstrate the effectiveness of the developed mathematical model. Results indicate that with increasing market numbers and final product numbers, the total objective function value and run time increase. In case that decision-makers are willing to deal with uncertainty with higher reliability, they should consider whole environmental conditions as input parameters. Therefore, when the number of scenarios increases, the total objective function value increases. Besides, the trade-off between cost function and other objective functions is studied. Also, the benefit of the stochastic programming approach is proved. To show the applicability of the proposed model, different modes are defined and compared with the proposed model, and the results demonstrate that the increasing use of recyclable parts and application of the recycling strategy yield more economic savings and less costs.

Originality/value

This paper aims to present a more comprehensive model based on real-world conditions for the supplier selection problem in green supply chain under uncertainty. In addition to economic issue, environmental issue is considered from different aspects such as selecting the environment-friendly suppliers, purchasing from them and taking the probability of defective finished products and goods from suppliers into account.
Insurer interest margin management, default risk, and life insurance policyholder protection
Authors: Lin Jyh-Horng , Li Xuelian , Huang Fu-Wei
Published: September 2018

Purpose

This paper aims to theoretically examine the effects of regulatory policyholder protection on spread behavior and default probability of a life insurance company.

Design/methodology/approach

The authors construct a contingent claim model for the valuation of the equity of a life insurance company. Then, they extend it to model default risk measures associated with a more appropriate behavioral mode of strategic invested asset rate-setting under regulation.

Findings

The findings established that the optimal insurer interest margin is explicitly modeled by a spread between the loan rate and the required guaranteed rate of the company. The effect of the guaranteed rate on the insurer interest margin is positive when the barrier is low, whereas it is negative when the barrier is high. As the barrier increases, the positive effect of the guaranteed rate on the default risk is increased, the negative effect of the participation on the insurer interest margin is decreased and the positive effect of the participation on the default risk is decreased.

Practical implications

Several results derived that should be of interest to investors, analysts, supervising agencies and policymakers. For example, policyholders protected by increasing the guaranteed rate may create a higher risk for the life insurance company to meet its obligations.

Originality/value

The authors’ approach is a significant departure from the existing literature; they differentiate among path-dependent, barrier options and suggest that the life insurance company’s defaults are more commonly triggered by regulatory responses than debt default.
How could discourse theories of identity formation critically engage patient-centered care in older adults?
Authors: Horton Anna , Horton Simon
Published: September 2018

Purpose

The purpose of this paper is to explore how discourse theories can contribute to the concept of identity formation within a patient- or person-centered care (PCC) orientation, to enable more critical engagement with PCC in older people.

Design/methodology/approach

This is a conceptual paper.

Findings

This paper concludes that the discourse literature has important insights for understanding identity formation in older people as operationalized in the context of PCC in three particular ways: accounting for multiplicity in patients’ identity; exploring “the devolution of responsibility” to address shifts in performing identities in clinical encounters; and attending to a “crisis of positioning” to engage empowerment discourse within a PCC philosophy.

Originality/value

Whilst a notion of patient identity is at the heart of PCC, the concept remains inconsistent and underdeveloped. This is particularly problematic for the quality of care in older adults, as PCC has become increasingly synonymous with care of older people. Discourse theories of identity formation can be used to critically engage with identity within the context of PCC, so as to develop more nuanced understandings of “the person” or “the patient,” with the potential to improve research into care for aging and older adults.
Assessing the social determinants of health care costs for Medicaid‐enrolled adolescents in Washington State using administrative data
Authors: Patton Deleena A. , Liu Qinghua , Adelson Jaimie D. , Lucenko Barbara A.
Published: September 2018

Objective

The study used administrative data to identify the social determinants that have the greatest impact on Medicaid expenditures in adolescence.

Data Sources

Data were compiled using the Washington State Department of Social and Health Services Integrated Client Databases, which link data from state systems including Medicaid claims and social services receipt.

Study Design

Medical system and behavioral health service costs of over 180 000 Medicaid‐enrolled adolescents aged 12‐17 were measured using integrated administrative data from Washington State. Social determinants of health, including child maltreatment and parent risk factors, were also measured. Two‐stage regression models were used to identify factors associated with increased health care utilization and costs.

Principal Findings

Regression models revealed that the factors most predictive of higher health care costs were child abuse, child neglect, and instability in out‐of‐home placements related to foster care. Other social determinants of health, such as parent risk factors, were not associated with health care costs. Child maltreatment and placement instability impacted health care costs primarily through large increases in behavioral health utilization and costs.

Conclusions

Prevention and early interventions for children and families to decrease child maltreatment and increase foster care placement stability could reduce overall health care costs.
Saving Impact of Mortgage Payments: A Microlevel Study for the U.S. Households
Authors: Güneş Ali , Tunç Cengiz
Published: September 2018

This article investigates the effect of the mortgage payments on the saving rate of the U.S. households by employing instrumental variable‐based methods along with the Panel Study Income Dynamics data over the period of 1999–2015. The results show that a 1% increase in the mortgage payments leads to a 0.15‐percentage‐point (corresponding to an actual 8.8%) decrease in the saving rate. The significant depressing effect also prevails even when mortgage payment is decomposed into the principal and interest components. The finding evidence indicates that the changes in the saving rate of the U.S. households can be partially explained by the changes in mortgage payments.