bluuebunny/crossref_metadata_2025_split huggingface dataset:
An optimal kernel‐based U‐statistic method for quantitative gene‐set association analysis
Authors: He Tao , Li Shaoyu , Zhong Ping‐Shou , Cui Yuehua 
Published: November 2018

AbstractSingle‐variant‐based genome‐wide association studies have successfully detected many genetic variants that are associated with a number of complex traits. However, their power is limited due to weak marginal signals and ignoring potential complex interactions among genetic variants. The set‐based strategy was proposed to provide a remedy where multiple genetic variants in a given set (e.g., gene or pathway) are jointly evaluated, so that the systematic effect of the set is considered. Among many, the kernel‐based testing (KBT) framework is one of the most popular and powerful methods in set‐based association studies. Given a set of candidate kernels, the method has been proposed to choose the one with the smallest p‐value. Such a method, however, can yield inflated Type 1 error, especially when the number of variants in a set is large. Alternatively one can get p values by permutations which, however, could be very time‐consuming. In this study, we proposed an efficient testing procedure that cannot only control Type 1 error rate but also have power close to the one obtained under the optimal kernel in the candidate kernel set, for quantitative trait association studies. Our method, a maximum kernel‐based U‐statistic method, is built upon the KBT framework and is based on asymptotic results under a high‐dimensional setting. Hence it can efficiently deal with the case where the number of variants in a set is much larger than the sample size. Both simulation and real data analysis demonstrate the advantages of the method compared with its counterparts.
Microglial modulation through colony‐stimulating factor‐1 receptor inhibition attenuates demyelination
Authors: Wies Mancini Victoria Sofía Berenice , Pasquini Juana María , Correale Jorge Daniel , Pasquini Laura Andrea 
Published: November 2018

AbstractMultiple sclerosis (MS) is one of the most common causes of progressive disability affecting young people with very few therapeutic options available for its progressive forms. Its pathophysiology involves demyelination and neurodegeneration apparently driven by microglial activation, which is physiologically dependent on colony‐stimulating factor‐1 receptor (CSF‐1R) signaling. In the present work, we used microglial modulation through oral administration of brain‐penetrant CSF‐1R inhibitor BLZ945 in acute and chronic cuprizone (CPZ)‐induced demyelination to evaluate preventive and therapeutic effects on de/remyelination and neurodegeneration. Our results show that BLZ945 induced a significant reduction in the number of microglia. Preventive BLZ945 treatment attenuated demyelination in the acute CPZ model, mainly in cortex and external capsule. In contrast, BLZ945 treatment in the acute CPZ model failed to protect myelin or foster remyelination in myelin‐rich areas, which may respond to a loss in microglial phagocytic capacity and the consequent impairment in oligodendroglial differentiation. Preventive and therapeutic BLZ945 treatment promoted remyelination and neuroprotection in the chronic model. These results could be potentially transferred to the treatment of progressive forms of MS.
π‐Dimerization ability of conjugated oligomer dication diradicaloids composed of dithienylpyrrole and benzodithiophene units
Authors: Akahane Takahiro , Takase Masayoshi , Mazaki Yasuhiro , Nishinaga Tohru 
Published: November 2018

AbstractStable conjugated oligomer dications 12+ and 22+ composed of 2,5‐di(2‐thienyl)‐N‐methylpyrrole (DTP) units at the both ends of the π‐systems with methoxy substituents at the 3‐position of thienyl units and methylthio end‐capping group and benzo[2,1‐b:3,4‐b′]dithiophene (BDT) unit(s) at the central part with sterically demanding phenyl substituents were synthesized. From DFT calculations and ESR experiments, it was concluded that the diradical character in 12+ and 22+ was reduced in comparison with the radical character of their reference compound 3·+ composed of one DTP and one BDT units. In addition, the shorter 12+ was considered to have a further lower diradical character than that of 22+. Nevertheless, judging from the results of VT‐UV‐vis‐NIR measurements, both 12+ and 22+ showed a comparable π‐dimerization ability at the DTP moiety in dichloromethane solution with 3·+.
Tuning of hydrogel stiffness using a two‐component peptide system for mammalian cell culture
Authors: Scelsi Alessandra , Bochicchio Brigida , Smith Andrew , Workman Victoria L. , Castillo Diaz Luis A. , Saiani Alberto , Pepe Antonietta 
Published: November 2018

AbstractSelf‐assembling peptide hydrogels (SAPHs) represent emerging cell cultures systems in several biomedical applications. The advantages of SAPHs are mainly ascribed to the absence of toxic chemical cross‐linkers, the presence of ECM‐like fibrillar structures and the possibility to produce hydrogels with a large range of different mechanical properties. We will present a two‐component peptide system with tuneable mechanical properties, consisting of a small pentapeptide (SFFSF‐NH2, SA5N) that acts as a gelator and a larger 21‐mer peptide (SFFSF‐GVPGVGVPGVG‐SFFSF, SA21) designed as a physical cross‐linker. The hydrogels formed by different mixtures of the two peptides are made up mainly of antiparallel β‐sheet nanofibers entangling in an intricate network. The effect of the addition of SA21 on the morphology of the hydrogels was investigated by atomic force microscopy and transmission electron microscopy and correlated to the mechanical properties of the hydrogel. Finally, the biocompatibility of the hydrogels using 2D cell cultures was tested. © 2018 The Authors. journal Of Biomedical Materials Research Part A Published By Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 535–544, 2019.
Mkx-Deficient Mice Exhibit Hedgehog Signaling–Dependent Ectopic Ossification in the Achilles Tendons
Authors: Liu Han , Xu Jingyue , Jiang Rulang 
Published: November 2018

ABSTRACT Heterotopic ossification is the abnormal formation of mineralized bone in skin, muscle, tendon, or other soft tissues. Tendon ossification often occurs from acute tendon injury or chronic tendon degeneration, for which current treatment relies heavily on surgical removal of the ectopic bony tissues. Unfortunately, surgery creates additional trauma, which often causes recurrence of heterotopic ossification. The molecular mechanisms of heterotopic ossification are not well understood. Previous studies demonstrate that Mkx is a transcription factor crucial for postnatal tendon fibril growth. Here we report that Mkx–/– mutant mice exhibit ectopic ossification in the Achilles tendon within 1 month after birth and the tendon ossification deteriorates with age. Genetic lineage labeling revealed that the tendon ossification in Mkx–/– mice resulted from aberrant differentiation of tendon progenitor cells. Furthermore, tissue-specific inactivation of Mkx in tendon cells postnatally resulted in a similar ossification phenotype, indicating that Mkx plays a key role in tendon tissue homeostasis. Moreover, we show that Hedgehog signaling is ectopically activated at early stages of tendon ossification and that tissue-specific inactivation of Smoothened, which encodes the obligatory transducer of Hedgehog signaling, in the tendon cell lineage prevented or dramatically reduced tendon ossification in Mkx–/– mice. Together, these studies establish a new genetic mouse model of tendon ossification and provide new insight into its pathogenic mechanisms. © 2018 American Society for Bone and Mineral Research.
PINK1/Parkin‐mediated mitophagy promotes apelin‐13‐induced vascular smooth muscle cell proliferation by AMPKα and exacerbates atherosclerotic lesions
Authors: He Lu , Zhou Qionglin , Huang Zheng , Xu Jin , Zhou Hong , Lv Deguan , Lu Liqun , Huang Shifang , Tang Mingzhu , Zhong Jiuchang , Chen Jian‐xiong , Luo Xuling , Li Lanfang , Chen Linxi 
Published: November 2018

AbstractAberrant proliferation of vascular smooth muscle cells (VSMC) is a critical contributor to the pathogenesis of atherosclerosis (AS). Our previous studies have demonstrated that apelin‐13/APJ confers a proliferative response in VSMC, however, its underlying mechanism remains elusive. In this study, we aimed to investigate the role of mitophagy in apelin‐13‐induced VSMC proliferation and atherosclerotic lesions in apolipoprotein E knockout (ApoE‐/‐) mice. Apelin‐13 enhances human aortic VSMC proliferation and proliferative regulator proliferating cell nuclear antigen expression in dose and time‐dependent manner, while is abolished by APJ antagonist F13A. We observe the engulfment of damage mitochondria by autophagosomes (mitophagy) of human aortic VSMC in apelin‐13 stimulation. Mechanistically, apelin‐13 increases p‐AMPKα and promotes mitophagic activity such as the LC3I to LC3II ratio, the increase of Beclin‐1 level and the decrease of p62 level. Importantly, the expressions of PINK1, Parkin, VDAC1, and Tom20 are induced by apelin‐13. Conversely, blockade of APJ by F13A abolishes these stimulatory effects. Human aortic VSMC transfected with AMPKα, PINK1, or Parkin and subjected to apelin‐13 impairs mitophagy and prevents proliferation. Additional, apelin‐13 not only increases the expression of Drp1 but also reduces the expressions of Mfn1, Mfn2, and OPA1. Remarkably, the mitochondrial division inhibitor‐1(Mdivi‐1), the pharmacological inhibition of Drp1, attenuates human aortic VSMC proliferation. Treatment of ApoE‐/‐ mice with apelin‐13 accelerates atherosclerotic lesions, increases p‐AMPKα and mitophagy in aortic wall in vivo. Finally, PINK1‐/‐ mutant mice with apelin‐13 attenuates atherosclerotic lesions along with defective in mitophagy. PINK1/Parkin‐mediated mitophagy promotes apelin‐13‐evoked human aortic VSMC proliferation by activating p‐AMPKα and exacerbates the progression of atherosclerotic lesions.
Annexin A3 gene silencing promotes myocardial cell repair through activation of the PI3K/Akt signaling pathway in rats with acute myocardial infarction
Authors: Meng Hua , Zhang Yan , An Song‐Tao , Chen Yan 
Published: November 2018

AbstractAcute myocardial infarction (AMI), as a severe consequence of coronary atherosclerotic heart disease, always contributes to the loss of myocardial cells. Mounting evidence shows that annexin protects the myocardium from ischemic injury. In this study, we examine the inhibition of annexin A3 (ANXA3) on AMI through the phosphatidylinositide 3‐kinase/protein kinase B (PI3K/Akt) signaling pathway. We selected rats to build an AMI model which was then assigned into different groups. The hemodynamic parameters after transfection were detected by using enzyme‐linked immunosorbent assay. The effect of silencing of ANXA3 on inflammatory reaction and the PI3K/Akt signaling pathway was assessed. Rats transfected with ANXA3‐short hairpin RNA had alleviated hemodynamics, inflammatory reaction, decreased infarct size, α‐smooth muscle actin, Collagen I, and Collagen III as well as an increased vascular endothelial growth factor. Silencing ANAX3 would promote repair and healing of myocardial tissue by activation of the PI3K/Akt signaling pathway. Collectively, our study provides evidence that the downregulation of ANXA3 promotes the repair and healing of myocardial tissues by activating the PI3K/Akt signaling pathway.
Echo‐tracking evaluation of changes in common carotid artery wall elasticity after smoking cessation
Authors: Zhang Pu , Guo Ruijun , Wang Chen , Xiao Dan , Qin Haiyan , Zhang Lingling 
Published: November 2018

AbstractThe aim of this study was to explore changes in the common carotid arterial wall elasticity after smoking cessation. Carotid artery ultrasonographic examination was performed in 136 patients, then 1 or 2 years after smoking cessation. We used echo‐tracking (ET) to measure stiffness index (β), pressure‐strain elasticity modulus (Ep), arterial compliance (AC), augmentation index (AI), and local pulse wave velocity (PWVβ). Patients were divided into four groups based on whether or not they successfully stopped smoking (groups M and N, respectively) and whether (groups M2 and N2, respectively) or not (groups M1 and N1, respectively) they showed comorbidities. In group M1, β, Ep and PWVβ were lower at 1 year than before smoking cessation, while AC and AI did not change. At 2 years, β, Ep, PWVβ, and AC, but not AI, improved further. In group M2, β, Ep, and PWVβ decreased at 2 years, whereas AC and AI did not change. In groups N1 and N2, none of the variables changed significantly. ET can be used quantitatively to evaluate the impact of smoking cessation on the elasticity of the common carotid artery wall.
IRF5 regulates unique subset of genes in dendritic cells during West Nile virus infection
Authors: Chow Kwan T , Driscoll Connor , Loo Yueh-Ming , Knoll Megan , Gale Michael 
Published: November 2018

Abstract
Pathogen recognition receptor (PRR) signaling is critical for triggering innate immune activation and the expression of immune response genes, including genes that impart restriction against virus replication. RIG-I-like receptors and TLRs are PRRs that signal immune activation and drive the expression of antiviral genes and the production of type I IFN leading to induction of IFN-stimulated genes, in part through the interferon regulatory factor (IRF) family of transcription factors. Previous studies with West Nile virus (WNV) showed that IRF3 and IRF7 regulate IFN expression in fibroblasts and neurons, whereas macrophages and dendritic cells (DCs) retained the ability to induce IFN-β in the absence of IRF3 and IRF7 in a manner implicating IRF5 in PRR signaling actions. Here we assessed the contribution of IRF5 to immune gene induction in response to WNV infection in DCs. We examined IRF5-dependent gene expression and found that loss of IRF5 in mice resulted in modest and subtle changes in the expression of WNV-regulated genes. Anti-IRF5 chromatin immunoprecipitation with next-generation sequencing of genomic DNA coupled with mRNA analysis revealed unique IRF5 binding motifs within the mouse genome that are distinct from the canonical IRF binding motif and that link with IRF5-target gene expression. Using integrative bioinformatics analyses, we identified new IRF5 primary target genes in DCs in response to virus infection. This study provides novel insights into the distinct and unique innate immune and immune gene regulatory program directed by IRF5.
IRF5 regulates distinct gene regulation programs associated with diverse cellular pathways following West Nile Virus infection in mouse dendritic cells.
Progression of hearing loss in neurofibromatosis type 2 according to genetic severity
Authors: Emmanouil Beatrice , Houston Rory , May Anne , Ramsden James D. , Hanemann C. Oliver , Halliday Dorothy , Parry Allyson , Mackeith Samuel 
Published: November 2018

Objectives/HypothesisThis study set out to describe the progression of hearing loss in patients with neurofibromatosis type 2 (NF2), treated in a quaternary multidisciplinary clinic. It also aimed to compare hearing loss across patients grouped according to a known genetic severity score to explore its utility for prognostication.Study DesignRetrospective cohort study.MethodsWe conducted a study of 147 patients with confirmed NF2 diagnosis for a mean observational period of 10 years. Pure‐tone average (PTA), optimum discriminations scores (ODS), and genotype data were collected. Patients were classified according to hearing class (American Academy of Otolaryngology), their candidacy for auditory implantation (UK National NF2 consensus) and grouped by genetic severity as: 1 = tissue mosaic, 2A = mild classic, 2B = moderate classic, and 3 = severe. Survival analysis investigated the effect of genetic severity on the age of loss of serviceable hearing.ResultsGenetic severity was a significant predictor of hearing outcomes such as ODS, hearing classification, and maximum annual PTA deterioration. Although the overall median age of loss of serviceable hearing was 78 years, there was significant variation according to the genetic severity; the median for severe patients was 32 years compared to a median of 80 for tissue mosaic patients.ConclusionsThis is the first description of long‐term hearing outcomes in a clinical setting across a large heterogeneous cohort of patients with NF2. The results highlight the potential importance and benefit of considering the genetic severity score of patients when undertaking treatment decisions, as well as planning future natural history studies.Level of Evidence2c Laryngoscope, 129:974–980, 2019
Short refutations for an equivalence‐chain principle for constant‐depth formulas
Authors: Buss Sam , Ramyaa Ramyaa 
Published: November 2018

AbstractWe consider tautologies expressing equivalence‐chain properties in the spirit of Thapen and Krajíček, which are candidates for exponentially separating depth k and depth Frege proof systems. We formulate a special case where the initial member of the equivalence chain is fully specified and the equivalence‐chain implications are actually equivalences. This special case is shown to lead to polynomial size resolution refutations. Thus it cannot be used for separating depth k and depth propositional systems. We state some Håstad switching lemma conditions that restrict the possible propositional proofs in more general situations.
Polymacrocycles Derived via Ugi Multi‐Component Reactions
Authors: Dannecker Patrick‐Kurt , Sehlinger Ansgar , Meier Michael A. R. 
Published: November 2018

AbstractThe synthesis of macrocycles based on the Ugi‐4CR has been thoroughly explored by Wessjohann and coworkers, while polymerizations utilizing the Ugi‐4CR are already patented by Ugi and recently studied more in detail, developing a new trend in polymer chemistry. Here, the combination of both, that is, the synthesis of polymacrocycles, is demonstrated. As diverse functional groups can be easily introduced in a macrocycle via Ugi‐4CR, a straightforward design of polymacrocycles is achieved in a two‐step procedure. First, the Ugi‐4CR of 10‐undecenoic acid, a diamine, a diisocyanide, and an aldehyde results in diversely substituted macrocycles having two terminal double bonds. Subsequently, these macrocycles are polymerized by ADMET (acyclic diene metathesis) or thiol‐ene polymerization to generate polymacrocycles with potential application in coordination chemistry as, for example, sensors, filters, or phase‐transfer catalysts. Moreover, the setup of the literature‐known Ugi macrocyclization is simplified by systematic reaction screening.
Modeling piecewise planar fault discontinuities without element‐partitioning in 3D reservoir‐geomechanical models
Authors: Liu Chuanqi , Prévost Jean H. , Sukumar N. 
Published: November 2018

SummaryUsing the extended finite element method, faults can be introduced into a three‐dimensional reservoir‐geomechanical model without meshing to assess the potential for fault reactivation associated with industrial activities such as disposal of CO2 or fluid extraction. The residuals to the governing equations include basis functions formed from the enrichment functions for strong and weak discontinuities. The traditional spatial integration scheme is based on an algorithm that partitions each enriched element into a collection of subtetrahedra, which is time and storage intensive. To avoid element partitioning, we adopt the homogeneous numerical integration scheme (referred as HNI hereafter) where the integration of homogeneous monomials over each polyhedron is converted into the integration of the same monomials over the one‐dimensional edges of the polyhedron by using Stokes's theorem and Euler's homogeneous function theorem. The integrands for the strong and weak discontinuities are derived to implement the integration scheme in the three‐dimensional reservoir‐geomechanical model. An example of a jagged fault is presented to reveal the advantages of HNI scheme over the standard element partitioning approach. Several other examples that involve fluid flow, fault sliding, and fault sliding triggered by injection pressure are also presented to demonstrate that accurate and efficient computations are realized by the new integration scheme.
Biodegradable polymer/clay systems for highly controlled release of NPK fertilizer
Authors: Daitx Tales S. , Giovanela Marcelo , Carli Larissa N. , Mauler Raquel S. 
Published: November 2018

The aim of this work was to obtain biodegradable polymeric systems based on poly(hydroxybutyrate) (PHB) for use in the controlled release of agrochemicals and to analyze the relationship between the properties of polymers and the rates of release of active compounds. Two types of systems were obtained: one using nitrogen, phosphorous, and potassium (NPK) fertilizer directly mixed within the polymer matrix and another with the fertilizer previously incorporated in bentonite (Bent) and mixed with the polymer. The systems were obtained by melt processing and then evaluated by their properties. The release of the active compounds was analyzed by conductometric analysis using an aqueous solution as release medium for 240 hours. The obtained results were correlated with the biodegradation process of PHB. All of the systems presented a significant reduction in the active compounds released to the environment as compared with the direct application of NPK. The PHB/NPK systems showed a release of up to 37% of the compounds, while the PHB/m‐Bent showed greater control, with a release between 4% and 11% after 240 hours. In addition, the properties of the polymer systems presented a direct relationship with the rate of active compounds released. The type of production process, properties, and biodegradability indicate interesting potential of these systems for application in the controlled release of active compounds.
Extremum seeking by a dynamic plant using mixed integral sliding mode controller with synchronous detection gradient estimation
Authors: Solis Cesar U. , Clempner Julio B. , Poznyak Alexander S. 
Published: November 2018

SummaryThis paper presents a continuous‐time optimization method for an unknown convex function restricted to a dynamic plant with an available output including a stochastic noise. For solving the problem, we propose an extremum seeking algorithm based on a modified synchronous detection method for computing a stochastic gradient descent approach. In order to reject from the beginning the undesirable uncertainties and perturbations of the dynamic plant, we employ the standard deterministic integral sliding mode control transforming the initial dynamic plant to the static one, and after (in fact, from the beginning of the process), we apply the gradient decedent technique. We consider time‐decreasing parameters for compensating the stochastic dynamics. We prove the stability and the mean‐square convergence of the method. To validate the exposition, we perform a numerical example simulation.
Conclusion
Authors: Lindsay Claire 
Published: November 2018

AbstractBy way of conclusion to the preceding arguments, this chapter, drawing on ideas from the new formalism and media studies history, pursues the implications of the magazines’ rhythm and serialization with respect to theories of nation-building in the context of post-revolutionary Mexico. In its summation of the ramifications of the book’s findings, it also returns to the suggestive idea of archive, first rehearsed in Chapter 1, to consider the concept’s material and epistemological value for this particular object of study.