bluuebunny/crossref_metadata_2025_split huggingface dataset:
LRRK2-phosphorylated Rab10 sequesters Myosin Va with RILPL2 during ciliogenesis blockade
Authors: Yanatori Izumi , Dhekne Herschel S. , Vides Edmundo G. , Sobu Yuriko , Diez Federico , Pfeffer Suzanne R. 
Published: April 2020

AbstractActivating mutations in LRRK2 kinase cause Parkinson’s disease. Pathogenic LRRK2 phosphorylates a subset of Rab GTPases and blocks ciliogenesis. Thus, defining novel phospho-Rab interacting partners is critical to our understanding of the molecular basis of LRRK2 pathogenesis. RILPL2 binds with strong preference to LRRK2-phosphorylated Rab8A and Rab10. RILPL2 is a binding partner of the motor protein and Rab effector, Myosin Va. We show here that the globular tail domain of Myosin Va also contains a high affinity binding site for LRRK2-phosphorylated Rab10, and certain tissue-specific Myosin Va isoforms strongly prefer to bind phosphorylated Rab10. In the presence of pathogenic LRRK2, RILPL2 relocalizes to the peri-centriolar region in a phosphoRab10- and Myosin Va-dependent manner. In the absence of phosphoRab10, expression of RILPL2 or depletion of Myosin Va increase centriolar RILPL2 levels, and either condition is sufficient to block ciliogenesis in RPE cells. These experiments show that LRRK2 generated phosphoRab10 dramatically redistributes Myosin Va-RILPL2 complexes to the mother centriole, which may sequester Myosin Va and RILPL2 in a manner that blocks their normal roles in ciliogenesis.
LPHN2 inhibits vascular permeability by differential control of endothelial cell adhesion
Authors: Camillo Chiara , Facchinello Nicola , Villari Giulia , Mana Giulia , Gioelli Noemi , Sandri Chiara , Astone Matteo , Tortarolo Dora , Clapero Fabiana , Gays Dafne , Oberkersch Roxana E. , Arese Marco , Tamagnone Luca , Valdembri Donatella , Santoro Massimo , Serini Guido 
Published: April 2020

ABSTRACTDynamic modulation of endothelial cell-to-cell and cell-to-extracellular matrix (ECM) adhesion is essential for blood vessel patterning and functioning. Yet, the molecular mechanisms involved in this process have not been completely deciphered. We identify the adhesion G protein-coupled receptor (ADGR) Latrophilin 2 (LPHN2) as a novel determinant of endothelial cell (EC) adhesion and barrier function. In cultured ECs, endogenous LPHN2 localizes at ECM contacts, signals through cAMP/Rap1, and inhibits focal adhesion (FA) formation and nuclear localization of YAP/TAZ transcriptional regulators, while promoting tight junction (TJ) assembly. ECs also express an endogenous LPHN2 ligand, fibronectin-leucine-rich transmembrane 2 (FLRT2), that prevents ECM-elicited EC behaviors in a LPHN2-dependent manner. Vascular ECs oflphn2aknock-out zebrafish embryos become abnormally stretched, display a hyperactive YAP/TAZ pathway, and lack proper intercellular TJs. Consistently, blood vessels are hyperpermeable and intravascularly injected cancer cells extravasate more easily inlphn2anull animals. Thus, LPHN2 ligands, such as FLRT2, may be therapeutically exploited to interfere with cancer metastatic dissemination.SUMMARYCamillo et al. show that the LPHN2 receptor, upon activation by FLRT2 ligand, inhibits focal adhesion formation and promotes tight junction assembly in endothelial cells. Blood vessels oflphn2anull animals are hyperpermeable and injected cancer cells extravasate more easily.
Dopaminergic Gene Dosage in Autism versus Developmental Delay: From Complex Networks to Machine Learning approaches
Authors: Santos André , Caramelo Francisco , de Melo Joana Barbosa , Castelo-Branco Miguel 
Published: April 2020

AbstractThe neural basis of behavioural changes in Autism Spectrum Disorders (ASD) remains a controversial issue. One factor contributing to this challenge is the phenotypic heterogeneity observed in ASD, which suggests that several different system disruptions may contribute to diverse patterns of impairment between and within study samples. Here, we took a retrospective approach, using SFARI data to study ASD by focusing on participants with genetic imbalances targeting the dopaminergic system. Using complex network analysis, we investigated the relations between participants, Gene Ontology (GO) and gene dosage related to dopaminergic neurotransmission from a polygenic point of view. We converted network analysis into a machine learning binary classification problem to differentiate ASD diagnosed participants from DD (developmental delay) diagnosed participants. Using 1846 participants to train a Random Forest algorithm, our best classifier achieved on average a diagnosis predicting accuracy of 85.18% (sd 1.11%) on a test sample of 790 participants using gene dosage features. In addition, we observed that if the classifier uses GO features it was also able to infer a correct response based on the previous examples because it is tied to a set of biological process, molecular functions and cellular components relevant to the problem. This yields a less variable and more compact set of features when comparing with gene dosage classifiers. Other facets of knowledge-based systems approaches addressing ASD through network analysis and machine learning, providing an interesting avenue of research for the future, are presented through the study.Lay SummaryThere are important issues in the differential diagnosis of Autism Spectrum Disorders. Gene dosage effects may be important in this context. In this work, we studied genetic alterations related to dopamine processes that could impact brain development and function of 2636 participants. On average, from a genetic sample we were able to correctly separate autism from developmental delay with an accuracy of 85%.
Tetramerisation of the CRISPR ring nuclease Csx3 facilitates cyclic oligoadenylate cleavage
Authors: Athukoralage Januka S. , McQuarrie Stuart , Grüschow Sabine , Graham Shirley , Gloster Tracey M. , White Malcolm F. 
Published: April 2020

AbstractType III CRISPR systems detect foreign RNA and activate the cyclase domain of the Cas10 subunit, generating cyclic oligoadenylate (cOA) molecules that act as a second messenger to signal infection, activating nucleases that degrade the nucleic acid of both invader and host. This can lead to dormancy or cell death; to avoid this, cells need a way to remove cOA from the cell once a viral infection has been defeated. Enzymes specialised for this task are known as ring nucleases, but are limited in their distribution. Here, we demonstrate that the widespread CRISPR associated protein Csx3, previously described as an RNA deadenylase, is a ring nuclease that rapidly degrades cyclic tetra-adenylate (cA4). The enzyme has an unusual cooperative reaction mechanism involving an active site that spans the interface between two dimers, sandwiching the cA4substrate. We propose the name Crn3 (CRISPR associated ring nuclease 3) for the Csx3 family.
Contrasting response of twoLotus corniculatusL. accessions to combined waterlogging-saline stress
Authors: Antonelli C.J. , Calzadilla P.I. , Campestre M.P. , Escaray F.J. , Ruiz O.A. 
Published: April 2020

AbstractWaterlogging and salinity impair crops growth and productivity worldwide, being their combined effects larger than the additive effects of both stresses separately. Recently, a newLotus corniculatusaccession has been collected from a coastal area with a high frequency of waterlogging-saline stress events. This population is diploid and has potential to increase nutritional values ofLotuscultivars used as forages. Due to its environmental niche, we hypothesize that this accession would show a better adaptation to combined waterlogging-saline stress compared to another commonly used tetraploidL. corniculatus(cv. San Gabriel). Shoot and root growth under waterlogging, salinity and combined waterlogging-saline treatments were addressed, together with chlorophyll fluorescence and gas exchange measurements. Results showed that salinity and waterlogging effects were more severe for the tetraploid accession, being the differences larger under the combined stress condition. In addition, Na+, Cl−and K+concentrations were measured in young and old leaves, and in roots. A larger accumulation of Na+and Cl−was observed under both saline and combined stress treatments for the tetraploidL. corniculatus, for which ion toxicity effects were evident. The expression of theNHX1andCLCgenes, coding for Na+and Cl−transporters respectively, was only increased in response to combined stress in the diploidL. corniculatusplants, suggesting that ion compartmentalization mechanisms were induced in this accession. As a conclusion, the recent characterizedL. corniculatusmight be used for the introduction of new tolerant traits to combined stresses, in otherLotusspecies used as forage.
LDpred2: better, faster, stronger
Authors: Privé Florian , Arbel Julyan , Vilhjálmsson Bjarni J. 
Published: April 2020

AbstractPolygenic scores have become a central tool in human genetics research. LDpred is a popular method for deriving polygenic scores based on summary statistics and a matrix of correlation between genetic variants. However, LDpred has limitations that may reduce its predictive performance. Here we present LDpred2, a new version of LDpred that addresses these issues. We also provide two new options in LDpred2: a “sparse” option that can learn effects that are exactly 0, and an “auto” option that directly learns the two LDpred parameters from data. We benchmark predictive performance of LDpred2 against the previous version on simulated and real data, demonstrating substantial improvements in robustness and predictive accuracy compared to LDpred1. We then show that LDpred2 also outperforms other polygenic score methods recently developed, with a mean AUC over the 8 real traits analyzed here of 65.1%, compared to 63.8% for lassosum, 62.9% for PRS-CS and 61.5% for SBayesR. Note that, in contrast to what was recommended in the first version of this paper, we now recommend to run LDpred2 genome-wide instead of per chromosome. LDpred2 is implemented in R package bigsnpr.
Tumor invasion as non-equilibrium phase separation
Authors: Kang Wenying , Ferruzzi Jacopo , Spatarelu Catalina-Paula , Han Yu Long , Sharma Yasha , Koehler Stephan A. , Mitchel Jennifer A. , Butler James P. , Roblyer Darren , Zaman Muhammad H. , Park Jin-Ah , Guo Ming , Chen Zi , Pegoraro Adrian F. , Fredberg Jeffrey J. 
Published: April 2020

ABSTRACTTumor invasion depends upon properties of both cells and of the extracellular matrix (ECM). Despite ample evidence that cancer cells can modulate their material state during invasion, underlying biophysical mechanisms remain unclear. Here, we show the potential for coexistence of – and transition between – solid-like, fluid-like, and gas-like phases in invading breast cancer spheroids. Epithelial spheroids are nearly jammed and solid-like in the core but unjam at the periphery to invade as a fluid-like collective. Conversely, post-metastatic spheroids are unjammed and fluid-like in the core and – depending on ECM density – can further unjam and invade as gas-like single cells, or re-jam to invade as a fluid-like collective. A novel jamming phase diagram predicts material phases that are superficially similar to inanimate systems at thermodynamic equilibrium, but here arising in living systems, which exist far from equilibrium. We suggest that non-equilibrium phase separation may provide a unifying physical picture of tumor invasion.TWO-SENTENCE SUMMARYUsing tumor spheroids invading into an engineered three-dimensional matrix, we show here that the cellular collective exhibits coexistent solid-like, fluid-like, and gas-like phases. The spheroid interior develops spatial and temporal heterogeneities in material phase which, depending upon cell type and matrix density, ultimately result in a variety of phase separation patterns at the invasive front, as captured by a jamming phase diagram.
Efficient gene-environment interaction tests for large biobank-scale sequencing studies
Authors: Wang Xinyu , Lim Elise , Liu Ching-Ti , Sung Yun Ju , Rao Dabeeru C. , Morrison Alanna C. , Boerwinkle Eric , Manning Alisa K. , Chen Han 
Published: April 2020

ABSTRACTComplex human diseases are affected by genetic and environmental risk factors and their interactions. Gene-environment interaction (GEI) tests for aggregate genetic variant sets have been developed in recent years. However, existing statistical methods become rate limiting for large biobank-scale sequencing studies with correlated samples. We propose efficient Mixed-model Association tests for GEne-Environment interactions (MAGEE), for testing GEI between an aggregate variant set and environmental exposures on quantitative and binary traits in large-scale sequencing studies with related individuals. Joint tests for the aggregate genetic main effects and GEI effects are also developed. A null generalized linear mixed model adjusting for covariates but without any genetic effects is fit only once in a whole genome GEI analysis, thereby vastly reducing the overall computational burden. Score tests for variant sets are performed as a combination of genetic burden and variance component tests by accounting for the genetic main effects using matrix projections. The computational complexity is dramatically reduced in a whole genome GEI analysis, which makes MAGEE scalable to hundreds of thousands of individuals. We applied MAGEE to the exome sequencing data of 41,144 related individuals from the UK Biobank, and the analysis of 18,970 protein coding genes finished within 10.4 CPU hours.
Cyber security and the disaster resilience framework
Authors: Panda Abhilash , Bower Andrew 
Published: April 2020

Purpose
The purpose of this paper is to concentrate on the place of cyber security risk in the framework of global commitments adopted in 2015 to reduce disaster risks in an all-hazards approach. It explores the correlations between traditional risks associated with critical infrastructures – as understood by the Sendai framework – cyber security risks and the cascading effects characteristic of today’s complex and interrelated shocks and stresses. It takes a step further, expanding the focus of traditionally understood technological risks to explore cyber security risks, at the heart of our societies’ digital transformations,and showcase opportunities from the European context.

Design/methodology/approach
By reviewing existing literature on cyber security, disaster resilience and cascading disasters, this paper highlights current challenges and good practices undertaken by various governments.

Findings
Understanding disaster risks is a precondition to improving the mitigation of impacts of existing risks and preventing new risks. Effective risk reduction relies on a solid understanding of losses resulting from events to inform future actions, and on the assessment of risks relying on a robust evidence base and state-of-the-art scientific capacity to model and simulate potential hazards. In this context, embedding cyber security risks, and the complexity of cascading impacts in improving the understanding of disaster risks, calls for appropriate methods and tools allowing for a multi-risk and holistic focus to the assessment of risks and the planning of risk management capacities that follow.

Research limitations/implications
Globally and in Europe, focus on interconnected risk and their impacts is steadily increasing. Risk assessments are still conservative; incorporation of cyber resilience into national and local level DRR plans is yet not visible.

Originality/value
Existing research is restricted to cyber security and disaster resilience, as separated subjects. This paper, for the first time, brings together the interconnection between the two topic options to address them.
Criteria for flood warning levels in Vietnam
Authors: Huong Huynh Thi Lan , Dzung Luong Huu 
Published: April 2020

Purpose
Determining alarm levels of river floods is considered an effective non-structural measure to prevent and mitigate the damages of flood and inundation. This study aims to propose a holistic approach, a comprehensive review of the factors affecting flooding and flood risk, based on which the water level (WL) is proposed for the flood alarm levels. The corresponding proposed WL to the necessary flood alarm levels is based on observed data, as well as simulated data from statistical methods and hydrological and hydraulic models.

Design/methodology/approach
In this paper, the proposed criteria to delineate WLs corresponding to flood alarm levels include flood magnitude; flood derivation and flood duration; flood risks and damage; correlation with neighboring stations; flood characteristics and local characteristics; and other criteria (flood prevention strategy and flood experience).

Findings
The paper proposed a synthesis approach to determine flood warning levels in Vietnam. The retrieved levels are the basics to revise the Decision 632/2010 of the Vietnam Government on determining water alarm levels for flood prevention. The study proposes a new flood alarm system including revised flood levels at 115 existing stations and new flood levels at 30 additional stations. The proposed flood warning level can help manage the flooding problem in major river systems that supports flood protection and prevention services in Vietnam.

Originality/value
The paper proposed a novel synthesis approach to flood prevention in Vietnam.
Exploring the effects of economic growth, population density and international trade on energy consumption and environmental quality in India
Authors: Rahman Mohammad Mafizur 
Published: April 2020

PurposeThis paper aims to investigate the effects of economic growth, population density and international trade on energy consumption and environmental quality in India.Design/methodology/approachTaking annual data of 1971-2011, autoregressive distributed lag bounds testing technique is applied to explore the long run link between the series. The Granger causality test is used to determine the direction of causality between the variables.FindingsThe obtained results confirm the cointegration of variables, and economic growth and population density are found to have significant positive effects on energy consumption in both the short and long runs. CO2emissions are also positively and significantly affected by population density and energy consumption, and negatively affected by economic growth.Originality/valueThe paper is original and valuable in the sense that it has considered two relevant additional explanatory variables, namely, population density and trade openness, which got little attention in the past. This research is an improvement over the previous studies because it has looked at the separate effects of explanatory variables on energy consumption, in addition to the effects on carbon emissions. Therefore, the findings of this research are more reliable because this adopted methodology is better and extensive, and the authors have properly addressed the issue of omitted variable bias.
The sustainable development of university student loans based on the evolutionary game
Authors: Zhang Yan , You Xiaoqiong , Wang Wenke , Lin Ting 
Published: April 2020

Purpose
National student loans help solve the problem of tuition fees for students from poor families to a great extent. This paper aims to study the behavior of three main players involved in university student loans, namely, universities, banks and students and explores necessary conditions for promoting the steady development of student loans, as well as the sustainability of cooperation and coordination among players, thus promoting the further development of student loans.

Design/methodology/approach
First, from the perspectives of the three related players of banks, students and universities and their behavior, this paper establishes a three-player behavioral evolutionary game model, conducts a sustainable game analysis among the different players, and by replicating the dynamic equations with the Jacobian matrix solve the evolutionarily stable strategy. Finally, applying MATLAB tools, a sensitivity analysis of relevant impacting factors is carried out to explore the influencing mechanism of the sustainable development of student loans.

Findings
To achieve the mechanism of mutual coordination and cooperation between participants, banks need to be guided to actively issue student loans and conduct strict loan review. College students should be encouraged to establish good credit and strengthen penalties should be implemented for violations of regulations. Universities should be encouraged to help banks reduce information asymmetry, promote financial knowledge and student integrity education and promote the sustainable development of national student loans.

Originality/value
This research will help scholars better understand the interaction mechanism among universities, banks and students, and promote the sustainable development of national student loans.
Long-term care in Spain: a reform failure or the regulation of a development path?
Authors: Aguilar-Hendrickson Manuel 
Published: April 2020

PurposeSpain departed from the Southern European tradition of residual long-term care services with the 2006 reform. The paper aims to present the main traits of the reform and its implementation, explores the reasons that may explain why the reform happened and to which extent and why it fell short of expectations.Design/methodology/approachThe article draws on available literature on the reform and on administrative data to present a complex and nuanced view of the reform process and its limits.FindingsThe reform was actually a measure to enhance and rationalize a preexisting process of social care services development, rather than the creation of a completely new care system. A rapid increase in female labor market participation since the 1990s and the looming demands of a late baby-boom and the subsequent fertility crash appear to be two key factors that explain both the previous development and its bolstering by the reform. The budgetary constraints of the Great Recession and governance problems, linked to a complex and sometimes dysfunctional multilevel governance arrangement, help to understand why the reform bogged down. Nevertheless, the overall balance is more nuanced, and significantly more services are provided 12 years after the reform.Originality/valueWhile many assessments of the reform have been negative, putting it into a larger context of social care development, the 2006 Dependency Act has contributed to a significant increase in expenditure and coverage. The impact of budgetary restrictions has been important, but other factors, such as governance arrangements, may explain more of the problems of the implementation.