bluuebunny/crossref_metadata_2025_split huggingface dataset:
Centenarian Controls Increase Variant Effect-sizes by an average two-fold in an Extreme Case-Extreme Control Analysis of Alzheimer’s Disease
Authors: Tesi Niccolò , van der Lee Sven J. , Hulsman Marc , Jansen Iris E. , Stringa Najada , van Schoor Natasja , Meijers-Heijboer Hanne , Huisman Martijn , Scheltens Philip , Reinders Marcel J.T. , van der Flier Wiesje M. , Holstege Henne 
Published: April 2018

AbstractThe detection of genetic loci associated with Alzheimer’s disease (AD) requires large numbers of cases and controls because variant effect-sizes are mostly small. We hypothesized that variant effect-sizes should increase when individuals who represent the extreme ends of a disease spectrum are considered, as their genomes are assumed to be maximally enriched or depleted with disease-associated genetic variants.We used 1,073 extensively phenotyped AD cases with relatively young age at onset as extreme cases (66.3±7.9 years), 1,664 age-matched controls (66.0±6.5 years) and 255 cognitively healthy centenarians as extreme controls (101.4±1.3 years). We estimated the effect-size of 29 variants that were previously associated with AD in genome-wide association studies.Comparing extreme AD-cases with centenarian-controls increased the variant effect-size relative to published effect-sizes by on average 1.90-fold (SE=0.29,p=9.0×10−4). The effect-size increase was largest for the rare high-impactTREM2 (R74H)variant (6.5-fold), and significant for variants in/nearECHDC3(4.6-fold),SLC24A4-RIN3(4.5-fold),NME8(3.8-fold),PLCG2(3.3-fold),APOE-ε2(2.2-fold) andAPOE-ε4(2.0-fold). Comparing extreme phenotypes enabled us to replicate the AD association for 10 variants (p<0.05) in relatively small samples. The increase in effect-sizes depended mainly on using centenarians as extreme controls: the average variant effect-size was not increased in a comparison of extreme AD cases and age-matched controls (0.94-fold,p=6.8×10−1), suggesting that on average the tested genetic variants did not explain the extremity of the AD-cases. Concluding, using centenarians as extreme controls in AD case-controls studies boosts the variant effect-size by on average two-fold, allowing the replication of disease-association in relatively small samples.
An integrative study on ribonucleoprotein condensates identifies scaffolding RNAs and reveals a new player in Fragile X-associated Tremor/Ataxia Syndrome
Authors: Cid-Samper Fernando , Gelabert-Baldrich Mariona , Lang Benjamin , Lorenzo-Gotor Nieves , Ponti Riccardo Delli , Severijnen Lies-Anne WFM , Bolognesi Benedetta , Gelpi Ellen , Hukema Renate K. , Botta-Orfila Teresa , Tartaglia Gian Gaetano 
Published: April 2018

SummaryRecent evidence indicates that specific RNAs promote formation of ribonucleoprotein condensates by acting as scaffolds for RNA-binding proteins (RBPs).We systematically investigated RNA-RBP interaction networks to understand ribonucleoprotein assembly. We found that highly-contacted RNAs are highly structured, have long untranslated regions (UTRs) and contain nucleotide repeat expansions. Among the RNAs with such properties, we identified the FMR1 3’ UTR that harbors CGG expansions implicated in Fragile X-associated Tremor/Ataxia Syndrome (FXTAS).We studied FMR1 binding partners in silico and in vitro and prioritized the splicing regulator TRA2A for further characterization. In a FXTAS cellular model we validated TRA2A-FRM1 interaction and investigated implications of its sequestration at both transcriptomic and post-transcriptomic levels. We found that TRA2A co-aggregates with FMR1 in a FXTAS mouse model and in post mortem human samples.Our integrative study identifies key components of ribonucleoprotein aggregates, providing links to neurodegenerative disease and allowing the discovery of new therapeutic targets.
Costless metabolic secretions as drivers of interspecies interactions in microbial ecosystems
Authors: Pacheco Alan R. , Moel Mauricio , Segrè Daniel 
Published: April 2018

ABSTRACTMetabolic exchange can mediate beneficial interactions among microbes, helping explain diversity in microbial communities. These interactions are often assumed to involve a fitness cost, prompting questions on how cooperative phenotypes can be stable and withstand the emergence of cheaters. Here we use genome-scale models of metabolism to investigate whether a radically different scenario, the pervasive release of “costless” metabolites (i.e. those that cause no fitness cost to the producing organism), can serve as a prominent mechanism for inter-microbial interactions. By carrying out over 1 million pairwise growth simulations for 14 microbial species in a combinatorial assortment of environmental conditions, we find that there is indeed a large space of metabolites that can be secreted at no cost, which can generate ample cross-feeding opportunities. In addition to providing an atlas of putative costless interdependencies, our modeling also demonstrates that oxygen availability significantly enhances mutualistic interactions by providing more opportunities for metabolic exchange through costless metabolites, resulting in an over-representation of specific ecological network motifs. In addition to helping explain natural diversity, we show how the exchange of costless metabolites can facilitate the engineering of stable synthetic microbial consortia.
Persistent coding of outcome-predictive cue features in the rat nucleus accumbens
Authors: Gmaz Jimmie M. , Carmichael James E. , van der Meer Matthijs A. A. 
Published: April 2018

AbstractThe nucleus accumbens (NAc) is important for learning from feedback, and for biasing and invigorating behavior in response to cues that predict motivationally relevant outcomes. NAc encodes outcome-related cue features such as the magnitude and identity of reward. However, little is known about how features of cues themselves are encoded. We designed a decision making task where rats learned multiple sets of outcome-predictive cues, and recorded single-unit activity in the NAc during performance. We found that coding of cue identity and location occurred alongside coding of expected outcome. Furthermore, this coding persisted both during a delay period, after the rat made a decision and was waiting for an outcome, and after the outcome was revealed. Encoding of cue features in the NAc may enable contextual modulation of ongoing behavior, and provide an eligibility trace of outcome-predictive stimuli for updating stimulus-outcome associations to inform future behavior.
Tensorial blind source separation for improved analysis of multi-omic data
Authors: Teschendorff Andrew E , Han Jing , Paul Dirk S , Virta Joni , Nordhausen Klaus 
Published: April 2018

AbstractThere is an increased need for integrative analyses of multi-omic data. Although several algorithms for analysing multi-omic data exist, no study has yet performed a detailed comparison of these methods in biologically relevant contexts. Here we benchmark a novel tensorial independent component analysis (tICA) algorithm against current state-of-the-art methods. Using simulated and real multi-omic data, we find that tICA outperforms established methods in identifying biological sources of data variation at a significantly reduced computational cost. Using two independent multi cell-type EWAS, we further demonstrate how tICA can identify, in the absence of genotype information, mQTLs at a higher sensitivity than competing multi-way algorithms. We validate mQTLs found with tICA in an independent set, and demonstrate that approximately 75% of mQTLs are independent of blood cell subtype. In an application to multi-omic cancer data, tICA identifies many gene modules whose expression variation across tumors is driven by copy number or DNA methylation changes, but whose deregulation relative to the normal state is independent such alterations, an important finding that we confirm by direct analysis of individual data types. In summary, tICA is a powerful novel algorithm for decomposing multi-omic data, which will be of great value to the research community.
Exosomes exploit the virus entry machinery and pathway to transmit IFN-α-induced antiviral activity
Authors: Yao Zhenlan , Li Xiaofang , Chen Jieliang , Qiao Yunsheng , Shen Fang , Shi Bisheng , Liu Jia , Ding Jiahui , Peng Lu , Li Jianhua , Yuan Zhenghong 
Published: April 2018

AbstractInterferon-α (IFN-α) induces the transfer of resistance to hepatitis B virus (HBV) from liver nonparenchymal cells (LNPCs) to hepatocytes via exosomes. However, little is known about the entry machinery and pathway involved in the transmission of IFN-α-induced antiviral activity. Here, we found that macrophage exosomes depend on T cell immunoglobulin and mucin receptor 1 (TIM-1), a hepatitis A virus (HAV) receptor, to enter hepatocytes for delivering IFN-α-induced anti-HBV activity. Moreover, two primary endocytic routes for virus infection, clathrin-mediated endocytosis (CME) and macropinocytosis, collaborate to permit exosome entry and anti-HBV activity transfer. Subsequently, lysobisphosphatidic acid (LBPA), an anionic lipid closely related to endosome penetration of virus, facilitates membrane fusion of exosomes in late endosomes/ multivesicular bodies (LEs/MVBs) and the accompanying exosomal cargo uncoating. Together, this study provides comprehensive insights into the transmission route of macrophage exosomes to efficiently deliver IFN-α-induced anti-HBV activity and highlights the similarities between the entry mechanisms of exosomes and virus.ImportanceOur previous study showed that LNPC-derived exosomes could transmit IFN-α-induced antiviral activity to HBV replicating hepatocytes, but the concrete transmission mechanisms which include exosome entry and exosomal cargo release remain unclear. In this study, we found that virus entry machinery and pathway were also applied to exosome-mediated cell-to-cell antiviral activity transfer. Macrophage-derived exosomes exploit hepatitis A virus receptor for access to hepatocytes. Later, CME and macropinocytosis are utilized by exosomes which is followed by exosome-endosome fusion for efficient transfer of IFN-α-induced anti-HBV activity. Dissecting the similarities between exosome and virus entry will be beneficial to designing exosomes as efficient vehicles for antiviral therapy.
Deleterious genetic variants inNOTCH1are a major contributor to the incidence of non-syndromic Tetralogy of Fallot
Authors: Page Donna J. , Miossec Matthieu J. , Williams Simon G. , Fotiou Elisavet , Monaghan Richard M. , Cordell Heather J. , Sutcliffe Louise , Topf Ana , Bourgey Mathieu , Bourque Guillaume , Eveleigh Robert , Dunwoodie Sally L. , Winlaw David S. , Bhattacharya Shoumo , Breckpot Jeroen , Devriendt Koenraad , Gewillig Marc , Brook David , Setchfield Kerry , Bu’Lock Frances A. , O’Sullivan John , Stuart Graham , Bezzina Connie , Mulder Barbara J.M. , Postma Alex V. , Bentham James R. , Baron Martin , Bhaskar Sanjeev S. , Black Graeme C. , Newman William G. , Hentges Kathryn E. , Lathrop Mark , Santibanez-Koref Mauro , Keavney Bernard D. 
Published: April 2018

AbstractAimsFamilial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, non-syndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease (CHD) phenotype. Rare genetic variants have been identified as important contributors to the risk of CHD, but relatively small numbers of TOF cases have been studied to date. Here, we use whole exome sequencing to assess the prevalence of rare, potentially deleterious variants in candidate genes previously associated with both syndromic and non-syndromic TOF, in the largest cohort of non-syndromic TOF patients reported to date.Methods & Results829 non-syndromic TOF patients underwent whole exome sequencing. A systematic review of the literature was conducted which revealed 77 genes in which mutations had been reported in patients with TOF. The presence of rare, deleterious variants in the 77 candidate genes was determined, defined by a minor allele frequency of ≤ 0.001 and scaled combined annotation-dependent depletion (CADD) score of ≥ 20. We found a clustering of heterozygous rare, deleterious variants inNOTCH1(P=1.89E-15),DOCK6(P=2.93E-07),MYOM2(P= 7.35E-05),TTC37(P=0.016),MESP1(P=0.024) andTBX1(P=0.039), after correcting for multiple testing.NOTCH1was most frequently found to harbour deleterious variants. Changes were observed in 49 patients (6%; 95% confidence interval [CI]: 4.5% - 7.8%) and included six truncating/frameshift variants and forty missense variants. Sanger sequencing of the unaffected parents of thirteen cases identified fivede novovariants. Variants were not confined to a single functional domain of the NOTCH1 protein but significant clustering of variants was evident in the EGF-like repeats (P=0.018). ThreeNOTCH1missense variants (p.G200R, p.C607Y andde novop.N1875S) were subjected to functional evaluation and showed a reduction in Jagged1 ligand-induced NOTCH signalling. p.C607Y, which exhibited the most significant reduction in signalling, also perturbed S1 cleavage of the NOTCH1 receptor in the Golgi.ConclusionTheNOTCH1locus is a frequent site of genetic variants predisposing to non-syndromic TOF with 6% of patients exhibiting rare, deleterious variants. Our data supports the polygenic origin of TOF and suggests larger studies may identify additional loci.
Phyla-specific Correlated Dynamics in Tropomyosin
Authors: James J.K. , Nanda V. 
Published: April 2018

ABSTRACTTropomyosin (Tpm) is a continuous α-helical coiled-coil homodimer that regulates actinomyosin interactions in muscle. We examined extended molecular simulations of four Tpms, two from the vertebrate phylum Chordata (rat and pig), and two from the invertebrate Arthropoda (shrimp and lobster), and found that despite extensive sequence and structural homologyacross metazoans, dynamic behavior – particularly long range structural fluctuations – were clearly distinct between phyla. Vertebrate Tpms were flexible and sampled complex, multi-state conformational landscapes. Invertebrate Tpms were rigid, sampling highly constrained harmonic landscapes. Filtering of trajectories by PCA into essential subspaces showed significant overlap within but not between phyla. In vertebrate Tpms, hinge-regions decoupled long-range inter-helical motions and suggested distinct domains. In contrast, crustacean Tpms lacked significant long range dynamic correlations – behaving more like a single rigid rod. Although Tpm sequence and structure has highly conserved over the last 0.6-billion years since the split of ancestral bilateria into protostomes and deuterostomes, divergence seems to have occurred at the level of long-range correlated dynamics, reflecting adaptations to phyla-specific requirements of actin binding and muscle contraction.
Automatic fault detection for Building Integrated Photovoltaic (BIPV) systems using time series methods
Authors: Shahandashti Mohsen , Ashuri Baabak , Mostaan Kia 
Published: April 2018

Purpose
Faults in the actual outdoor performance of Building Integrated Photovoltaic (BIPV) systems can go unnoticed for several months since the energy productions are subject to significant variations that could mask faulty behaviors. Even large BIPV energy deficits could be hard to detect. The purpose of this paper is to develop a cost-effective approach to automatically detect faults in the energy productions of BIPV systems using historical BIPV energy productions as the only source of information that is typically collected in all BIPV systems.

Design/methodology/approach
Energy productions of BIPV systems are time series in nature. Therefore, time series methods are used to automatically detect two categories of faults (outliers and structure changes) in the monthly energy productions of BIPV systems. The research methodology consists of the automatic detection of outliers in energy productions, and automatic detection of structure changes in energy productions.

Findings
The proposed approach is applied to detect faults in the monthly energy productions of 89 BIPV systems. The results confirm that outliers and structure changes can be automatically detected in the monthly energy productions of BIPV systems using time series methods in presence of short-term variations, monthly seasonality, and long-term degradation in performance.

Originality/value
Unlike existing methods, the proposed approach does not require performance ratio calculation, operating condition data, such as solar irradiation, or the output of neighboring BIPV systems. It only uses the historical information about the BIPV energy productions to distinguish between faults and other time series properties including seasonality, short-term variations, and degradation trends.
Modeling a transformational route to infrastructure sustainability in South Africa
Authors: Isa Rasheed , Emuze Fidelis , Das Dillip , Awuzie Bankole Osita 
Published: April 2018

Purpose
The purpose of this paper is to propose a model for operationalizing the integrated use of lean and sustainability concepts for infrastructure delivery. This model is premised on the need for the attainment of a sustainable built environment through efficient infrastructure delivery.

Design/methodology/approach
A case study research design was used in assessing five purposively selected cases within Gauteng province in South Africa. These facilities attained Green Building Council of South Africa ratings of 5- to 6-star, for the rating of green buildings and available evidence of integration of lean principles at the developmental stage. Questionnaires were administered to project’s role-players and semi-structured interviews were conducted with the users and facility managers, in order to elicit data for the model development. Questionnaire survey was adopted for the model validation.

Findings
The lean-sustainability platform for infrastructure delivery demonstrates features such as resources, drivers, barriers, activities, outputs, the results, and the ultimate impact. The findings give insight into various components of the model. It validates its robustness and highlights leadership among other critical factors necessary for successful operationalization of the lean-sustainability ethos required to transform the delivery of infrastructure.

Practical implications
The developed model provides a transformational route for achieving infrastructure sustainability. The lean-sustainable indicators identified will serve as evaluation tools for assessing lean-sustainability ethos during the delivery phases of infrastructure projects.

Originality/value
The model provides a new way of thinking about infrastructure project delivery regarding the need to promote sustainability in the built environment.
Governance in the Sendai: a way ahead?
Authors: Raju Emmanuel , da Costa Karen 
Published: April 2018

Purpose
The purpose of this paper is to identify how governance and accountability have been addressed in the Sendai Framework for Disaster Risk Reduction (SFDRR) 2015-2030.

Design/methodology/approach
The research is mainly based on the analysis of the SFDRR; scientific literature, particularly recent publications covering the SFDRR. The paper also takes into account grey literature.

Findings
The SFDRR does address issues of governance and accountability in disasters. However, more needs to be done to translate it into practice – particularly with regard to accountability.

Originality/value
The paper covers a topic that has not attracted considerable academic attention, despite the fact that the need to address accountability in disaster risk management, notably in DRR, has been generally acknowledged. By addressing governance and accountability in the most recent international DRR framework the paper adds value to the literature.
Determinants of building consistent human resources management systems
Authors: García-Carbonell Natalia , Martín-Alcázar Fernando , Sanchez-Gardey Gonzalo 
Published: April 2018

Purpose
While previous human resources management (HRM) studies have focused on human resources (HR) practices to explain the strategic HRM-performance link, organizational communication is studied as a key HRM process and an alternative perspective explains the factors influencing communication implementation and subsequently internal HRM system consistency. The paper aims to discuss these issues.

Design/methodology/approach
HR decision makers’ human capital is examined as a determinant of communication implementation by applying the partial least squares approach to a sample of 120 Spanish HR managers.

Findings
The results confirm the relevance of HR decision makers’ cognitive skills, showing that communication of HRM strategy does not appear to require a particular cognitive approach but rather a balance of creative and rational skills. Additionally, the findings suggest that appropriate communication implementation improves the internal consistency of the HRM system by creating coherent HR messages about the implemented practices.

Originality/value
This study presents three main contributions: analyzing conditions that promote more appropriate communication implementation; providing a process perspective instead of the traditional content focus to explain HRM, and deepening the ways in which communication affects the internal consistency of the HRM system.
Valuation of employment decision criteria
Authors: Gajderowicz Tomasz 
Published: April 2018

Purpose
The purpose of this paper is to expand our understanding of the decisions on labour supply, with particular attention given to the role of conditions of a contract between an employer and an employee. In the paper the value, from the employee’s perspective, of different characteristics of an employment contract are assessed.

Design/methodology/approach
Discrete choice experiment methodology is applied to evaluate employment attributes. Using data from a dedicated survey of students and graduates of social sciences in Poland, parameters of the employment-related utility function are estimated with a multinomial logit model and random parameter logistic regression. Due to the opt-out alternative in the design, reservation wages for different types of contracts are calculated.

Findings
The paper suggests that development conditions and psychological aspects of work are extremely important for employees’ decisions and their reservation wages.

Research limitations/implications
Due to limitations related to data generation process, generalisation of the results to the whole population is not possible.

Practical implications
The results of the study may help to develop tools of contract optimisation and remuneration systems. Such tools might lead to improvements in the efficiency of contracts in the labour market by simultaneously reducing employment costs and increasing workers’ utility.

Originality/value
The analysis of preferences and reservation wages contributes to our understanding of the observed wage differentials. It also helps to understand some apparent paradoxes of the labour supply behaviour, which are impossible to explain within the traditional approach to wage modelling.