bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aging and neurodegeneration are associated with increased mutations in single human neurons
Authors: Lodato Michael A. , Rodin Rachel E. , Bohrson Craig L. , Coulter Michael E. , Barton Alison R. , Kwon Minseok , Sherman Maxwell A. , Vitzthum Carl M. , Luquette Lovelace J. , Yandava Chandri , Yang Pengwei , Chittenden Thomas W. , Hatem Nicole E. , Ryu Steven C. , Woodworth Mollie B. , Park Peter J. , Walsh Christopher A. 
Published: December 2017

SummaryIt has long been hypothesized that aging and neurodegeneration are associated with somatic mutation in neurons; however, methodological hurdles have prevented testing this hypothesis directly. We used single-cell whole-genome sequencing to perform genome-wide somatic single-nucleotide variant (sSNV) identification on DNA from 161 single neurons from the prefrontal cortex and hippocampus of fifteen normal individuals (aged 4 months to 82 years) as well as nine individuals affected by early-onset neurodegeneration due to genetic disorders of DNA repair (Cockayne syndrome and Xeroderma pigmentosum). sSNVs increased approximately linearly with age in both areas (with a higher rate in hippocampus) and were more abundant in neurodegenerative disease. The accumulation of somatic mutations with age—which we term genosenium—shows age-related, region-related, and disease-related molecular signatures, and may be important in other human age-associated conditions.One-Sentence SummarySomatic single-nucleotide variants accumulate in human neurons in aging with regional specificity and in progeroid diseases.
Loss of the intellectual disability and autism gene Cc2d1a and its homolog Cc2d1b differentially affect spatial memory, anxiety, and hyperactivity
Authors: Zamarbide Marta , Oaks Adam W. , Pond Heather L. , Adelman Julia S. , Manzini M. Chiara 
Published: December 2017

ABSTRACTHundreds of genes are mutated in non-syndromic intellectual disability (ID) and autism spectrum disorder (ASD), with each gene often involved in only a handful of cases. Such heterogeneity can be daunting, but rare recessive loss of function (LOF) mutations can be a good starting point to provide insight into the mechanisms of neurodevelopmental disease. Biallelic LOF mutations in the signaling scaffold CC2D1A cause a rare form of autosomal recessive ID, sometimes associated with ASD and seizures. In parallel, we recently reported that Cc2d1a-deficient mice present with cognitive and social deficits, hyperactivity and anxiety. In Drosophila loss of the only ortholog of Cc2d1a, lgd, is embryonic lethal, while in vertebrates Cc2d1a has a homolog Cc2d1b which appears to be compensating, indicating that Cc2d1a and Cc2d1b have redundant function in humans and mice. Here, we generate an allelic series of Cc2d1a and Cc2d1b loss of function to determine the relative role of these genes during behavioral development. We generated Cc2d1b knockout (KO), Cc2d1a/1b double heterozygous and double KO mice, then performed behavioral studies to analyze learning and memory, social interactions, anxiety, and hyperactivity. We found that Cc2d1a and Cc2d1b have partially overlapping roles. Overall, loss of Cc2d1b is less severe than loss of Cc2d1a, only leading to cognitive deficits, while Cc2d1a/1b double heterozygous animals are similar to Cc2d1a-deficient mice. These results will help us better understand the deficits in individuals with CC2D1A mutations, suggesting that recessive CC2D1B mutations and trans-heterozygous CC2D1A and CC2D1B mutations could also contribute to the genetics of ID.
Detecting cancer vulnerabilities through gene networks under purifying selection in 4,700 cancer genomes
Authors: Gupta Anika , Horn Heiko , Razaz Parisa , Kim April , Lawrence Michael , Getz Gad , Lage Kasper 
Published: December 2017

ABSTRACTLarge-scale cancer sequencing studies have uncovered dozens of mutations critical to cancer initiation and progression. However, a significant proportion of genes linked to tumor propagation remain hidden, often due to noise in sequencing data confounding low frequency alterations. Further, genes in networks under purifying selection (NPS), or those that are mutated in cancers less frequently than would be expected by chance, may play crucial roles in sustaining cancers but have largely been overlooked. We describe here a statistical framework that identifies genes that have a first order protein interaction network significantly depleted for mutations, to elucidate key genetic contributors to cancers. Not reliant on and thus, unbiased by, the gene of interest’s mutation rate, our approach has identified 685 putative genes linked to cancer development. Comparative analysis indicates statistically significant enrichment of NPS genes in previously validated cancer vulnerability gene sets, while further identifying novel cancer-specific candidate gene targets. As more tumor genomes are sequenced, integrating systems level mutation data through this network approach should become increasingly useful in pinpointing gene targets for cancer diagnosis and treatment.
Exponential fluorescent amplification of individual RNAs using clampFISH probes
Authors: Rouhanifard Sara H. , Mellis Ian A. , Dunagin Margaret , Bayatpour Sareh , Symmons Orsolya , Cote Allison , Raj Arjun 
Published: December 2017

AbstractNon-enzymatic, high-gain signal amplification methods with single-cell, single-molecule resolution are in great need. We present click-amplifying FISH (clampFISH) for the fluorescent detection of RNA that combines the specificity of oligonucleotides with bioorthogonal click chemistry in order to achieve high specificity and extremely high-gain (>400x) signal amplification. We show that clampFISH signal enables detection with low magnification microscopy and separation of cells by RNA levels via flow cytometry. Additionally, we show that the modular design of clampFISH probes enables multiplexing, that the locking mechanism prevents probe detachment in expansion microscopy, and that clampFISH works in tissue samples.
The ventral stream receives spatial information from the dorsal stream during configural face processing
Authors: Zachariou Valentinos , Mlynaryk Nicole , Vernet Marine , Ungerleider Leslie G. 
Published: December 2017

AbstractConfigural face processing is considered to be vital for face perception. If configural face processing requires an evaluation of spatial information, might this process involve interactions between ventral stream face-processing regions and dorsal stream visuospatial-processing regions? We explored this possibility using thetaburst stimulation (TBS) with fMRI in humans. Participants were shown two faces that differed in either the shape (featural differences) or the spatial configuration (configural differences) of their features. TBS applied on dorsal location-processing regions: 1) reduced fMRI activity within ventral stream face-processing regions during configural but not featural face processing; and 2) reduced functional connectivity between these face regions significantly more for configural than featural face processing. No changes occurred when TBS was delivered on the vertex control site for either face task. We conclude that ventral stream face-processing regions receive visuospatial information from dorsal stream location-processing regions during configural face processing.Significance statementFace perception is thought to be mediated exclusively by neural substrates within the ventral visual pathway. However, by using non-invasive brain stimulation (thetabust transcranial magnetic stimulation) in healthy human adults, we demonstrate that the face-processing regions of the ventral visual pathway receive information from visuospatial-processing regions of the dorsal visual pathway during configural face processing, a vital function in face perception. Our findings thus indicate that veridical face perception may depend on both the ventral and dorsal visual pathways.
Inference about causation between body mass index and DNA methylation in blood from a twin family study
Authors: Li Shuai , Wong Ee Ming , Bui Minh , Nguyen Tuong L , Eric Joo Ji-Hoon , Stone Jennifer , Dite Gillian S , Dugué Pierre-Antoine , Milne Roger L , Giles Graham G , Saffery Richard , Southey Melissa C , Hopper John L 
Published: December 2017

AbstractBackgroundSeveral studies have reported DNA methylation in blood to be associated with body mass index (BMI), but only a few have investigated causal aspects of the association. We used a twin family design to assess this association at two life points and applied a novel analytical approach to investigate the evidence for causality.MethodsThe methylation profile of DNA from peripheral blood was measured for 479 Australian women (mean age 56 years) from 130 twin families. Linear regression was used to estimate the associations of methylation at ~410 000 cytosine-guanine dinucleotides (CpG), and of the average methylation at ~20 000 genes, with current BMI, BMI at age 18-21 years, and the change between the two (BMI change). A novel regression-based methodology for twins, Inference about Causation through Examination of Familial Confounding (ICE FALCON), was used to assess causation.ResultsAt 5% false discovery rate, nine, six and 12 CpGs at 24 loci were associated with current BMI, BMI at age 18-21 years and BMI change, respectively. The average methylation ofBHLHE40andSOCS3loci was associated with current BMI, and ofPHGDHlocus was associated with BMI change. From the ICE FALCON analyses with BMI as the predictor and methylation as the outcome, a woman’s methylation level was associated with her co-twin’s BMI, and the association disappeared conditioning on her own BMI, consistent with BMI causing methylation. To the contrary, using methylation as the predictor and BMI as the outcome, a woman’s BMI was not associated with her co-twin’s methylation level, consistent with methylation not causing BMI.ConclusionFor middle-aged women, peripheral blood DNA methylation at several genomic locations is associated with current BMI, BMI at age 18-21 years and BMI change. Our study suggests that BMI has a causal effect on peripheral blood DNA methylation.
On the proportional abundance of species: Integrating population genetics and community ecology
Authors: Marquet Pablo A. , Espinoza Guillermo , Abades Sebastian R. , Ganz Angela , Rebolledo Rolando 
Published: December 2017

ABSTRACTThe frequency of genes in interconnected populations and of species in interconnected communities are affected by similar processes, such as birth, death and immigration. The equilibrium distribution of gene frequencies in structured populations is known since the 1930s, under Wright’s metapopulation model known as the island model. The equivalent distribution for the species frequency (i.e. the species proportional abundance distribution (SPAD), at the metacommunity level, however, is unknown. In this contribution, we develop a stochastic model to analytically account for this distribution (SPAD). We show that the same as for genes SPAD follows a beta distribution, which provides a good description of empirical data and applies across a continuum of scales. This stochastic model, based upon a diffusion approximation, provides an alternative to neutral models for the species abundance distribution (SAD), which focus on number of individuals instead of proportions, and demonstrate that the relative frequency of genes in local populations and of species within communities follow the same probability law. We hope our contribution will help stimulate the mathematical and conceptual integration of theories in genetics and ecology.
Determining cell fate specification and genetic contribution to cardiac disease risk in hiPSC-derived cardiomyocytes at single cell resolution
Authors: Nguyen Quan H. , Lukowski Samuel W. , Chiu Han Sheng , Friedman Clayton E. , Senabouth Anne , Crowhurst Liam , Bruxmer Timothy J.C , Christ Angelika N. , Palpant Nathan J. , Powell Joseph E. 
Published: December 2017

AbstractThe majority of genetic loci underlying common disease risk act through changing genome regulation, and are routinely linked to expression quantitative trait loci, where gene expression is measured using bulk populations of mature cells. A crucial step that is missing is evidence of variation in the expression of these genes as cells progress from a pluripotent to mature state. This is especially important for cardiovascular disease, as the majority of cardiac cells have limited properties for renewal postneonatal. To investigate the dynamic changes in gene expression across the cardiac lineage, we generated RNA-sequencing data captured from 43,168 single cells progressing through in vitro cardiac-directed differentiation from pluripotency. We developed a novel and generalized unsupervised cell clustering approach and a machine learning method for prediction of cell transition. Using these methods, we were able to reconstruct the cell fate choices as cells transition from a pluripotent state to mature cardiomyocytes, uncovering intermediate cell populations that do not progress to maturity, and distinct cell trajectories that terminate in cardiomyocytes that differ in their contractile forces. Second, we identify new gene markers that denote lineage specification and demonstrate a substantial increase in their utility for cell identification over current pluripotent and cardiogenic markers. By integrating results from analysis of the single cell lineage RNA-sequence data with population-based GWAS of cardiovascular disease and cardiac tissue eQTLs, we show that the pathogenicity of disease-associated genes is highly dynamic as cells transition across their developmental lineage, and exhibit variation between cell fate trajectories. Through the integration of single cell RNA-sequence data with population-scale genetic data we have identified genes significantly altered at cell specification events providing insights into a context-dependent role in cardiovascular disease risk. This study provides a valuable data resource focused on in vitro cardiomyocyte differentiation to understand cardiac disease coupled with new analytical methods with broad applications to single-cell data.
Managing coastal risks at the Wadden Sea: a societal perspective
Authors: Gerkensmeier Birgit , Ratter Beate M.W. , Vollmer Manfred , Walsh Cormac 
Published: December 2017

PurposeThe trilateral Wadden Sea Region (WSR), extending from Den Helder in the Netherlands, along the German North Sea coast, to Esbjerg in Denmark, constitutes a unique but vulnerable coastal landscape. Vulnerability to environmental and societal risks is expected to increase in coming decades with encompassing new challenges such as demographic changes and conflicting uses of space, both on land and at sea. Meeting these challenges will require a shift toward an understanding of risk management as a social process, marking a significant departure from the dominant technical risk management paradigm. The paper aims to discuss these issues.Design/methodology/approachIn practice, this paradigm shift requires participatory stakeholder engagement, bringing together multiple and diverse perspectives, interests and concerns. This paper aims to support the implementation and expansion of enhanced social processes in coastal risk management by presenting a case study of participatory risk management process. Implemented in collaboration with a trilateral stakeholder partnership, the authors present a mixed-method approach which encouraged a joint, deliberate approach to environmental and societal risks within an overall framework.FindingsThe results enable the authors to deduce implications of participatory risk management processes for the WSR, wherein the partnership can act as a communicator and ambassador for an improved understanding of risk management as a social process.Originality/valueIn this context, the trilateral dimension, discussed here for the first time in relation with coastal risk management processes in the WSR, is emphasized as an efficient level that offers room for enhanced participatory and negotiation processes that are crucial for enhanced risk management processes.
The role of religious beliefs and practices in disaster
Authors: Gianisa Adisaputri , Le De Loic 
Published: December 2017

PurposeOver the last few years, there has been an increase of research interest on the role of religion in disaster. While some emphasize the positive role of religions during and after disasters, others rather point out that religion may lead to low perception of risk and create a fatalistic attitude in the face of such events. The purpose of this paper is to contribute to the vivid debate on the role of religious beliefs and practices in disaster response and recovery, using the earthquake that hit Padang city in Indonesia in 2009.Design/methodology/approachA review of reports and policy documents published by the government and non-government organizations was done to understand external aid provided during and after the 2009 earthquake. Fieldwork was conducted from April to May 2016 in Padang city. Interviews were done with religious followers and leaders of the Muslim community, as the main religion in the country, and Confucians community, as the biggest minority in the area.FindingsDrawing on interviews done with religious followers and leaders, the study highlights that religious beliefs and practices bond local people together and contributed to successful coping with disasters. It also emphasizes that religious communities can fill response and recovery gaps, such as when external intervention is limited.Practical implicationsReligious beliefs and practices, combined with other mechanisms, should be integrated within disaster risk reduction disaster management and activities as this would help build more resilient communities.Originality/valueIndonesia is a country where religion is very important, being the biggest Muslim country worldwide. It is also highly vulnerable to natural-hazards related disasters. Yet, little research has been done in Indonesia on the role of religion during and after disasters. This paper aims to explore the role of religious beliefs and practices in disasters in the area where religion plays an important role in people’s everyday life.
Staging option application to residential development: real options approach
Authors: Mintah Kwabena , Higgins David , Callanan Judith , Wakefield Ron 
Published: December 2017

Purpose
Real option valuation is capable of accounting for uncertainties in residential development projects but still lacks practical adoption due to limited evidence to support application of the theory in practice. The purpose of this paper is to use option valuation to value staging option embedded in residential projects and compare with results from DCF to determine which of the two methods delivers superior results.

Design/methodology/approach
The fuzzy payoff method (FPOM), a real options model that uses scenario planning approach to generate a range of figures, from which a single-numerical value is computed for decision-making.

Findings
The results showed that the use of a range of figures was able to represent uncertainties to a higher degree of accuracy than the static DCF. As a result, the FPOM was able to capture about 3 per cent of the value of the project that was missed by the DCF. The staging option offers an opportunity to abandon unprofitable phases of a project, thereby limiting downside losses. Thus, real option models are practically applicable to cases in property sector.

Practical implications
Residential property developers must consider flexibility in financial feasibility evaluation of development because of the embedded value in uncertain property projects. It is important to account for optionality in financial evaluation of property projects for value maximisation.

Originality/value
The FPOM has been used for the first time to evaluate a horizontal phasing of a residential development project.
Loose and tight coupling in educational organizations – an integrative literature review
Authors: Hautala Tanja , Helander Jaakko , Korhonen Vesa 
Published: December 2017

Purpose
The purpose of this paper is to review and synthesize the attributes of loose and tight coupling in educational organizations. In addition, it is aimed to determine whether this phenomenon has value and strategies to offer for the current educational administration and research.

Design/methodology/approach
Integrative literature review and content analysis, assisted by Atlas.ti software, were used as the methods of this paper. Review data included 32 articles from peer reviewed journals.

Findings
Conceptual framework of continuum of organizational couplings in educational organizations was generated. Elements of the framework include the features of coupling concepts within the continuum, components of couplings, contributory types of organizational couplings and the elements of leadership and change process with emerging strategies, as well as the element of cultural context. In this paper, elements of continuum of couplings and leadership will be emphasized.

Practical implications
Findings have practical implications for the management and leadership in educational organizations, and for the researchers in the field for future research purposes.

Social implications
Findings have social implications for both teaching staff and administration in educational organizations, by highlighting the attributes of loose and tight coupling, and their connections with leadership, change process and cultural context.

Originality/value
The paper presents a distinctive synopsis of the educational administration literature, in the context of loose and tight coupling, with the time span of four decades.
Principal influence in teacher hiring: documenting decentralization over time
Authors: Engel Mimi , Cannata Marisa , Curran F. Chris 
Published: December 2017

PurposeOver the past decade, policy researchers and advocates have called for the decentralization of teacher hiring decisions from district offices to school principals. The purpose of this paper is to document the trends across two and a half decades in principals’ reported influence over teacher hiring decisions in the USA and explore how and whether principal influence varies systematically across contexts.Design/methodology/approachRegression analysis with secondary data using seven waves of nationally representative data from the Schools and Staffing Survey.FindingsPrincipals report increased influence over the 25 years that the data span. While principals of urban schools were much more likely to report having less influence over teacher hiring compared to their non-urban counterparts in the late 1980s and early 1990s, their reported influence increased more than that of other principals.Research limitations/implicationsEmpowering principals as primary decision-makers assumes that they have the best information on which to make hiring decisions. At the same time, other research suggests that local teacher labor market dynamics contribute to the inequitable sorting of teachers across schools. This study raises questions regarding the implications of the increased influence of principals in teacher hiring on equity of access to quality teachers across schools.Originality/valueThis is the first study to explore whether and how principal influence in teacher hiring decisions has changed over time.