bluuebunny/crossref_metadata_2025_split huggingface dataset:
Seizures cause sustained microvascular constriction associated with astrocytic and vascular smooth muscle Ca2+ recruitment
Authors: Tran Cam Ha T. , George Antis G. , Teskey G. Campbell , Gordon Grant R. 
Published: June 2019

AbstractPreviously we showed that seizures result in a severe hypoperfusion/hypoxic attack that results in postictal memory and behavioral impairments (Farrell et al., 2016). However, neither postictal changes in microvasculature nor Ca2+ changes in key cell-types controlling blood perfusion have been visualized in vivo, leaving essential components of the underlying cellular mechanisms unclear. Here we use two-photon microvascular and Ca2+ imaging in awake mice to show that seizures result in a robust vasoconstriction of cortical penetrating arterioles, which temporally mirrors the prolonged postictal hypoxia. The vascular effect was dependent on cyclooxygenase-2, as pre-treatment with ibuprofen prevented postictal vasoconstriction. Seizures caused a rapid elevation in astrocyte endfoot Ca2+ that was confined to the seizure period. Vascular smooth muscle cells displayed a significant increase in Ca2+ both during and following seizures, lasting up to 75 minutes. The temporal activities of two cell-types within the neurovascular unit lead to seizure-induced hypoxia.HighlightsSeizures lead to equivalent levels of postictal hypoxia in both male and female miceCalcium elevation in astrocyte endfeet is confined to the seizurePostictal vasoconstriction in awake mice is mediated by cyclooxygenase-2Calcium elevation in vascular smooth muscle cells is enduring and correlates with vasoconstriction.
Ultrafast immunostaining of organ-scale tissues for scalable proteomic phenotyping
Authors: Yun Dae Hee , Park Young-Gyun , Cho Jae Hun , Kamentsky Lee , Evans Nicholas B. , Albanese Alex , Xie Katherine , Swaney Justin , Sohn Chang Ho , Tian Yuxuan , Zhang Qiangge , Drummond Gabi , Guan Webster , DiNapoli Nicholas , Choi Heejin , Jung Hae-Yoon , Ruelas Luzdary , Feng Guoping , Chung Kwanghun 
Published: June 2019

ABSTRACTStudying the function and dysfunction of complex biological systems necessitates comprehensive understanding of individual cells. Advancements in three-dimensional (3D) tissue processing and imaging modalities have enabled rapid visualization and phenotyping of cells in their spatial context. However, system-wide interrogation of individual cells within large intact tissue remains challenging, low throughput, and error-prone owing to the lack of robust labeling technologies. Here we introduce a rapid, versatile, and scalable method, eFLASH, that enables complete and uniform labeling of organ-scale tissue within one day. eFLASH dynamically modulates chemical transport and reaction kinetics to establish system-wide uniform labeling conditions throughout the day-long labeling period. This unique approach enables the same protocol to be compatible with a wide range of tissue types and probes, enabling combinatorial molecular phenotyping across different organs and species. We applied eFLASH to generate quantitative maps of various cell types in mouse brains. We also demonstrated multidimensional cell profiling in a marmoset brain block. We envision that eFLASH will spur holistic phenotyping of emerging animal models and disease models to help assess their functions and dysfunctions.
CEP290 myosin-tail homology domain is essential for protein confinement between inner and outer segments in photoreceptors
Authors: Datta Poppy , Hendrickson Brandon , Brendalen Sarah , Ruffcorn Avri , Seo Seongjin 
Published: June 2019

ABSTRACTMutations inCEP290cause various ciliopathies involving retinal degeneration. CEP290 proteins localize to the ciliary transition zone and are thought to act as a gatekeeper that controls ciliary protein trafficking. However, precise roles of CEP290 in photoreceptors and pathomechanisms of retinal degeneration inCEP290-associated ciliopathies are not sufficiently understood. UsingCep290conditional mutant mice, in which the C-terminal myosin-tail homology domain is disrupted after the connecting cilium is assembled, we show that CEP290, more specifically the myosin-tail homology domain of CEP290, is essential for protein confinement between the inner and the outer segments. Inner segment plasma membrane proteins including STX3, SNAP25, and IMPG2 rapidly accumulate in the outer segment upon disruption of the myosin-tail homology domain. In contrast, localization of endomembrane proteins is not altered. Trafficking and confinement of most outer segment-resident proteins appear to be unaffected or only minimally affected in this mouse model. One notable exception is RHO, which exhibits severe mislocalization to inner segments from the initial stage of degeneration. Similar mislocalization phenotypes were observed inrd16mice. These results suggest that failure of protein confinement at the connecting cilium and consequent accumulation of inner segment membrane proteins in the outer segment combined with insufficient RHO delivery is part of the disease mechanisms that cause retinal degeneration inCEP290-associated ciliopathies. Our study provides insights into the pathomechanisms of retinal degenerations associated with compromised ciliary gates.
The genetic architecture of fitness drives population viability during rapid environmental change
Authors: Kardos Marty ,   Northwest Fisheries Science Center, Luikart Gordon 
Published: June 2019

AbstractThe rapid global loss of biodiversity calls for improved predictions of how populations will evolve and respond demographically to ongoing environmental change. The heritability (h2) of selected traits has long been known to affect evolutionary and demographic responses to environmental change. However, effects of the genetic architecture underlying theh2of a selected trait on population responses to selection are less well understood. We use deterministic models and stochastic simulations to show that the genetic architecture underlyingh2can dramatically affect population viability during environmental change. Polygenic trait architectures (many loci, each with a small phenotypic effect) conferred higher population viability than genetic architectures with the same initialh2and large-effect loci under a wide range of scenarios. Population viability also depended strongly on the initial frequency of large-effect beneficial alleles, with moderately low initial allele frequencies conferring higher viability than rare or already-frequent large-effect alleles. Greater population viability associated with polygenic architectures appears to be due to higher short term evolutionary potential compared to architectures with large-effect loci. These results suggest that integrating information on the trait genetic architecture into quantitiative genetic and population viability analysis will substantially improve our understanding and prediction of evolutionary and demographic responses following environmental change.
Smoking and blood DNA methylation: novel associations, replication of previous findings and assessment of reversibility
Authors: Dugué Pierre-Antoine , Jung Chol-Hee , Joo JiHoon E , Wang Xiaochuan , Wong Ee Ming , Makalic Enes , Schmidt Daniel F , Baglietto Laura , Severi Gianluca , Southey Melissa C , English Dallas R , Giles Graham G , Milne Roger L 
Published: June 2019

ABSTRACTWe conducted a genome-wide association study of blood DNA methylation and smoking, attempted replication of previously discovered associations, and assessed the reversibility of smoking-associated methylation changes. DNA methylation was measured in baseline peripheral blood samples for 5,044 participants in the Melbourne Collaborative Cohort Study. For 1,032 participants, these measures were repeated using blood samples collected at follow-up, a median of 11 years later. A cross-sectional analysis of the association between smoking and DNA methylation and a longitudinal analysis of changes in smoking status and changes in DNA methylation were conducted. We used our cross-sectional analysis to replicate previously reported associations for current (N=3,327) and former (N=172) smoking. A comprehensive smoking index accounting for the bioactivity of smoking and several aspects of smoking history was constructed to assess the reversibility of smoking-induced methylation changes. We identified 4,496 cross-sectional associations at P<10−7, including 3,296 that were novel. We replicated the majority (90%) of previously reported associations for current and former smokers. In our data, we observed for former smokers a substantial degree of return to the methylation levels of never smokers, compared with current smokers (median: 74%, IQR=63-86%). Consistent with this, we found wide-ranging estimates for the half-life parameter of the comprehensive smoking index. Longitudinal analyses identified 368 sites at which methylation changed upon smoking cessation. Our study provides evidence of many novel associations between smoking and DNA methylation at CpGs across the genome, replicates the vast majority of previously reported associations, and indicates wide-ranging reversibility rates for smoking-induced methylation changes.
Disorder mediated oligomerization of DISC1 proteins revealed by coarse-grained computer simulations
Authors: Roche Julien , Potoyan Davit A 
Published: June 2019

AbstractDisrupted-in-Schizophrenia-1 (DISC1) is a scaffold protein of significant importance for neurodevelopment and a prominent candidate protein in the etiology of mental disorders. In this work, we investigate the role of conformational heterogeneity and local structural disorder in the oligomerization pathway of the full-length DISC1 and of two truncation variants. Through extensive coarse-grained molecular dynamics simulations with a predictive energy landscape based model, we reveal the general mechanistic principles of DISC1 oligomerization. We found that both conformational heterogeneity and structural disorder play an important role in the dimerization pathway of DISC1. This study sheds light on the differences in oligomerization pathways of the full-length protein compared to the truncated variants produced by a chromosomal translocation associated with schizophrenia.
Polyamine biosynthesis inXenopus laevis:the gene xlAZIN2/xlODC2 encodes a lysine decarboxylase
Authors: Lambertos Ana , Peñafiel Rafael 
Published: June 2019

AbstractOrnithine decarboxylase (ODC) is a key enzyme in the biosynthesis of polyamines, organic cations that are implicated in many cellular processes. The enzyme is regulated at the post-translational level by an unusual system that includes antizymes (AZs) and antizyme inhibitors (AZINs). Most studies on this complex regulatory mechanism have been focused on human and rodent cells, showing that AZINs (AZIN1 and AZIN2) are homologues of ODC but devoid of enzymatic activity. Little is known aboutXenopusODC and its paralogues, in spite of the relevance ofXenopusas a model organism for biomedical research. We have used the information existing in different genomic databases to compare the functional properties of the amphibian ODC1, AZIN1 and AZIN2/ODC2, by means of transient transfection experiments of HEK293T cells. Whereas the properties of xlODC1 and xlAZIN1 were similar to those reported for their mammalian orthologues, xlAZIN2/xlODC2 showed important differences with respect to human and mouse AZIN2. xlAZIN2 did not behave as an antizyme inhibitor, but it rather acts as an authentic decarboxylase forming cadaverine, due to its affinity for L-lysine as substrate; so, in accordance with this, it should be named as lysine decarboxylase (LDC). In addition, AZ1 stimulated the degradation of xlAZIN2 by the proteasome, but the removal of the 21 amino acid C-terminal tail, with a sequence quite different to that of mouse or human ODC, made the protein resistant to degradation. Collectively, our results indicate that inXenopusthere is only one antizyme inhibitor (xlAZIN1) and two decarboxylases, xlODC1 and xlLDC, with clear preferences for L-ornithine and L-lysine, respectively.
CurviPicker: a continuum robot for pick-and-place tasks
Authors: Yang Zhixiong , Zhao Bin , Bo Liang , Zhu Xiangyang , Xu Kai 
Published: June 2019

Purpose
Pick-and-place tasks are common across many industrial sectors, and many rigid-linked robots have been proposed for this application. This paper aims to alternatively present the development of a continuum robot for low-load medium-speed pick-and-place tasks.

Design/methodology/approach
An inversion of a previously proposed dual continuum mechanism, as a key design element, was used to realize the horizontal movements of the CurviPicker’s end effector. A flexible shaft was inserted to realize rotation and translation about a vertical axis. The design concept, kinematics, system descriptions and proof-of-concept experimental characterizations are elaborated.

Findings
Experimental characterizations show that the CurviPicker can achieve satisfactory accuracy after motion calibration. The CurviPicker is easy to control due to its simple kinematics, while its structural compliance makes it safe to work with, as well as less sensitive to possible target picking position errors to avoid damaging itself or the to-be-picked objects.

Research limitations/implications
The vertical translation of the CurviPicker is currently realized by moving the flexible shaft. Insertion of the flexible shaft introduces possible disturbances. It is desired to explore other form of variations to use structural deformation to realize the vertical translation.

Practical implications
The proposed CurviPicker realizes the Schöenflies motions via a simple structure. Such a robot can be used to increase robot presence and automation in small businesses for low-load medium-speed pick-and-place tasks.

Originality/value
To the best of the authors’ knowledge, the CurviPicker is the first continuum robot designed and constructed for pick-and-place tasks. The originality stems from the concept, kinematics, development and proof-of-concept experimental characterizations of the CurviPicker.
Multidisciplinary wing design of a light long endurance UAV
Authors: Grendysa Wojciech 
Published: June 2019

Purpose
The purpose of this paper is finding the optimal geometric parameters and developing of a method for optimizing a light unmanned aerial vehicle (UAV) wing, maximizing, at the same time, its endurance with the assumed parameters of aircraft mission.

Design/methodology/approach
The research is based on the experience gained by the author’s contribution to the project of building medium-altitude, long-endurance class, light UAV called “Samonit”. The author was responsible for the structure design, wind tunnel tests and flight tests of the “Samonit” aircraft. Based on the experience, the author was able to develop an optimization process considering various disciplines involved in the whole aircraft design topics such as aerodynamics, flight mechanics, structural stiffness and weight, aircraft stability and maneuverability. The presented methodology has a multidisciplinary nature, as in the process of optimization both aerodynamic aspects and the influence of wing geometric parameters on the wing structure and weight and the aircraft payload were taken into account. The optimal wing configuration was obtained using the genetic algorithms.

Findings
As a result, a set of wing geometrical parameters has been obtained that allowed for achieving twice as long endurance as compared with the initial one.

Practical implications
Using the methodology presented in the paper, an aircraft designer can easily find the optimum wing configuration of a designed aircraft, satisfying the mission requirements in a best way.

Originality/value
An original procedure has been developed, based on the actual design, wind tunnel tests and numerical calculations of “Samonit” aircraft, enabling the determination of optimum wing configuration for a small unmanned aircraft.
Development of an equivalent static method for the approximation of the dynamic response of offshore structures
Authors: Koukouselis Apostolos , Chatziioannou Konstantinos , Mistakidis Euripidis , Katsardi Vanessa 
Published: June 2019

Purpose
The design of compliant towers in deep waters is greatly affected by their dynamic response to wave loads as well as by the geometrical and material nonlinearities that appear. In general, a nonlinear time history dynamic analysis is the most appropriate one to be applied to capture the exact response of the structure under wave loading. However, this type of analysis is complex and time-consuming. This paper aims to develop a simplified methodology, which can adequately approximate the maximum response yielded by a dynamic analysis by means of a static analysis.

Design/methodology/approach
Various types of time history dynamic analysis are first applied on a detailed structural model, ranging from linear to fully nonlinear, that are used as reference solutions. In the sequel, a simplified analysis model is formulated, capable of reproducing the response of the entire structure with significantly reduced computational cost. In the next stage, this model is used to obtain the linear and nonlinear response spectra of the structure. Finally, these spectra are used to formulate a simplified design approach, based on equivalent static loads.

Findings
This simplified design approach produces good results in cases that the response is mainly governed by the first eigenmode, which is the case when compliant towers are considered.

Originality/value
The present paper borrows ideas from the area of earthquake engineering, where simplified methodologies can be used for the design of a certain class of structures. However, the development of a simplified methodology for the approximation of the dynamic behavior of offshore structures under wave loading is a much more complex problem, which, to the authors’ knowledge, has not been addressed till now.
The double-edged effect of knowledge search on innovation generations
Authors: Wang Chunhsien , Chen Min-Nan , Chang Ching-Hsing 
Published: June 2019

PurposeThe purpose of this paper is to investigate alliance partner diversity (APD) as a driving force that potentially enhances firms’ innovation generation (IG) in interfirm open alliance contexts. The authors propose that APD enhances IG but that the effects depend on both alliance network position and the double-edged external knowledge search strategy. Building on the knowledge-based view and social capital theory, the authors formally model how external knowledge search strategies can lead to productive or destructive acquisitions of external knowledge in interfirm open alliance networks. The authors theorize that when an individual firm adopts a central position in a complex interfirm open alliance network, its propensity toward beneficial IG depends on its knowledge search strategy (i.e. its breadth and depth) due to the joint influence of network position and knowledge search strategy on innovation.Design/methodology/approachUsing an original large-scale survey of high-tech firms, this study shows that the relationship between partner diversity and IG is contingent on a firm’s network position and knowledge search strategy. The authors also offer an original analysis of how knowledge search strategy (i.e. its breadth and depth) in network centrality (NC) affects the efficacy of knowledge acquisition in interfirm open alliance networks. Empirically, the authors provide an original contribution to the open innovation literature by integrating social capital and knowledge-based theory to rigorously measure firm IG.FindingsOverall, our findings suggest that the knowledge search strategy imparts a double-edged effect that may promote or interfere with external knowledge in IG in the context of the diversity of alliance partners.Research limitations/implicationsThe work has important limitations, such as its analysis of a single industry in the empirical models. Therefore, further studies should consider multiple industries that may provide useful insights into innovation decisions.Practical implicationsExternal knowledge search is valuable, particularly in the high-tech industry, as external knowledge acquisition generates innovation output. This study serves to raise managers’ awareness of various approaches to external knowledge searches and highlights the importance of network position in knowledge acquisition from interfirm open alliance collaborations.Originality/valueThis paper is the first to investigate the double-edged effect of knowledge search on interfirm open alliance networks. It also contributes to the theoretical and practical literature on interfirm open alliance networks by reflecting on external knowledge search and underlying network centrality and APD factors.
Support perceptions, flexible work options and career outcomes
Authors: Shanmugam Merlin Mythili , Agarwal Bhawna 
Published: June 2019

Purpose
This study aims to explore the leaky pipeline issue (attrition of working women due to motherhood) in the Indian information technology (IT) sector. The study analyses the effect of organisational and supervisory support perceptions on the use of flexible work options and its relationship with career outcomes in terms of job satisfaction, work-life conflict and turnover intentions.

Design/methodology/approach
A survey questionnaire to test the hypotheses was returned by 203 working women of the Indian IT sector belonging to three categories, namely, women undergoing treatment for infertility, pregnant women and women who had recently given birth at the time of the survey.

Findings
The findings state that the use of flexible work options significantly reduce work-life conflict, decrease the intention to turnover and increase job satisfaction, with organisational and supervisory perceptions playing a significant moderating role.

Research limitations/implications
The findings are based on self-reported responses. Nevertheless, the study provides insights into the work-life priorities of Indian women at the time of motherhood and opens up specific research opportunities to address the leaky pipeline due to pregnancy and childbirth.

Practical implications
Organisations should take genuine initiatives to effectively use the flexible work options and provide supervisory training for increased sensitivity to help reduce role conflict and let working women make informed choices in their careers and lives at the time of childbirth.

Originality/value
The paper could be the first known paper to study this special category of working women at the threshold of motherhood in the Indian IT sector.