bluuebunny/crossref_metadata_2025_split huggingface dataset:
Data-driven models of dominantly-inherited Alzheimer’s disease progression
Authors: Oxtoby Neil P. , Young Alexandra L. , Cash David M. , Benzinger Tammie L. S. , Fagan Anne M. , Morris John C. , Bateman Randall J. , Fox Nick C. , Schott Jonathan M. , Alexander Daniel C. 
Published: January 2018

AbstractDominantly-inherited Alzheimer’s disease is widely hoped to hold the key to developing interventions for sporadic late onset Alzheimer’s disease. We use emerging techniques in generative data-driven disease-progression modelling to characterise dominantly-inherited Alzheimer’s disease progression with unprecedented resolution, and without relying upon familial estimates of years until symptom onset (EYO). We retrospectively analysed biomarker data from the sixth data freeze of the Dominantly Inherited Alzheimer Network observational study, including measures of amyloid proteins and neurofibrillary tangles in the brain, regional brain volumes and cortical thicknesses, brain glucose hypometabolism, and cognitive performance from the Mini-Mental State Examination (all adjusted for age, years of education, sex, and head size, as appropriate). Data included 338 participants with known mutation status (211 mutation carriers: 163PSEN1; 17PSEN2; and 31APP) and a baseline visit (age 19–66; up to four visits each, 1·1 ± 1·9 years in duration; spanning 30 years before, to 21 years after, parental age of symptom onset). We used an event-based model to estimate sequences of biomarker changes from baseline data across disease subtypes (mutation groups), and a differential-equation model to estimate biomarker trajectories from longitudinal data (up to 66 mutation carriers, all subtypes combined). The two models concur that biomarker abnormality proceeds as follows: amyloid deposition in cortical then sub-cortical regions (approximately 24±11 years before onset); CSF p-tau (17±8 years), tau and Aβ42 changes; neurodegeneration first in the putamen and nucleus accumbens (up to 6 ± 2 years); then cognitive decline (7 ± 6 years), cerebral hypometabolism (4 ± 4 years), and further regional neurodegeneration. Our models predicted symptom onset more accurately than EYO: root-mean-squared error of 1·35 years versus 5·54 years. The models reveal hidden detail on dominantly-inherited Alzheimer’s disease progression, as well as providing data-driven systems for fine-grained patient staging and prediction of symptom onset with great potential utility in clinical trials.
Molecular crypsis by pathogenic fungi using human factor H. A numerical model
Authors: Lang Stefan , Germerodt Sebastian , Glock Christina , Skerka Christine , Zipfel Peter F. , Schuster Stefan 
Published: January 2018

AbstractMolecular mimicry is the formation of specific molecules by microbial pathogens to avoid recognition and attack by the immune system of the host. Several pathogenic Ascomycota and Zygomycota show such a behaviour by utilizing human complement factor H to hide in the blood stream. We call this type of mimicry molecular crypsis. Such a crypsis can reach a point where the immune system can no longer clearly distinguish between self and non-self cells. Thus, a trade-off between attacking disguised pathogens and erroneously attacking host cells has to be made, which can lead to autoreactivity. Based on signalling theory and protein-interaction modelling, we here present a mathematical model of molecular crypsis of pathogenic fungi using the example ofCandida albicans. We tackle the question whether perfect crypsis is feasible, which would imply that protection of human cells by complement factors would be useless. The model identifies pathogen abundance relative to host cell abundance as the predominant factor influencing successful or unsuccessful molecular crypsis. If pathogen cells gain a (locally) quantitative advantage over host cells, even autoreactivity may occur. Our new model enables insights into the mechanisms of candidiasis-induced sepsis and complement associated autoimmune diseases.
Mitogenomic data indicate admixture components of Asian Hun and Srubnaya origin in the Hungarian Conquerors
Authors: Neparáczki Endre , Maróti Zoltán , Kalmár Tibor , Kocsy Klaudia , Maár Kitti , Bihari Péter , Nagy István , Fóthi Erzsébet , Pap Ildikó , Kustár Ágnes , Pálfi György , Raskó István , Zink Albert , Török Tibor 
Published: January 2018

AbstractIt has been widely accepted that the Finno-Ugric Hungarian language, originated from proto Uralic people, was brought into the Carpathian Basin by the Hungarian Conquerors. From the middle of the 19thcentury this view prevailed against the deep-rooted Hungarian Hun tradition, maintained in folk memory as well as in Hungarian and foreign written medieval sources, which claimed that Hungarians were kinsfolk of the Huns. In order to shed light on the genetic origin of the Conquerors we sequenced 102 mitogenomes from early Conqueror cemeteries and compared them to sequences of all available databases. We applied novel population genetic algorithms, named Shared Haplogroup Distance and MITOMIX, to reveal past admixture of maternal lineages. Phylogenetic and population genetic analysis indicated that more than one third of the Conqueror maternal lineages were derived from Central-Inner Asia and their most probable ultimate sources were the Asian Huns. The rest of the lineages most likely originated from the Bronze Age Potapovka-Poltavka-Srubnaya cultures of the Pontic-Caspian steppe, which area was part of the later European Hun empire. Our data give support to the Hungarian Hun tradition and provides indirect evidence for the genetic connection between Asian and European Huns. Available data imply that the Conquerors did not have a major contribution to the gene pool of the Carpathian Basin, raising doubts about the Conqueror origin of Hungarian language.
Single-Cell Transcriptome Analysis of Lineage Diversity and Microenvironment in High-Grade Glioma
Authors: Yuan Jinzhou , Levitin Hanna Mendes , Frattini Veronique , Bush Erin C. , Boyett Deborah M. , Samanamud Jorge , Ceccarelli Michele , Dovas Athanassios , Zanazzi George , Canoll Peter , Bruce Jeffrey N. , Lasorella Anna , Iavarone Antonio , Sims Peter A. 
Published: January 2018

ABSTRACTBackgroundDespite extensive molecular characterization, we lack a comprehensive understanding of lineage identity, differentiation, and proliferation in high-grade gliomas (HGGs). We sampled the cellular milieu of HGGs with massively-parallel single-cell RNA-Seq.ResultsWhile HGG cells can resemble glia or even immature neurons and form branched lineage structures, mesenchymal transformation results in unstructured populations. Glioma cells in a subset of mesenchymal tumors lose their neural lineage identity, express inflammatory genes, and co-exist with marked myeloid infiltration, reminiscent of molecular interactions between glioma and immune cells established in animal models. Additionally, we discovered a tight coupling between lineage resemblance and proliferation among malignantly transformed cells. Glioma cells that resemble oligodendrocyte progenitors, which proliferate in the brain, are often found in the cell cycle. Conversely, glioma cells that resemble astrocytes, neuroblasts, and oligodendrocytes, which are non-proliferative in the brain, are generally non-cycling in tumors.ConclusionsThese studies reveal a relationship between cellular identity and proliferation in HGG and distinct population structures that reflects the extent of neural and non-neural lineage resemblance among malignantly transformed cells.
Genomic risk prediction of coronary artery disease in nearly 500,000 adults: implications for early screening and primary prevention
Authors: Inouye Michael , Abraham Gad , Nelson Christopher P. , Wood Angela M. , Sweeting Michael J. , Dudbridge Frank , Lai Florence Y. , Kaptoge Stephen , Brozynska Marta , Wang Tingting , Ye Shu , Webb Thomas R , Rutter Martin K. , Tzoulaki Ioanna , Patel Riyaz S. , Loos Ruth J.F. , Keavney Bernard , Hemingway Harry , Thompson John , Watkins Hugh , Deloukas Panos , Angelantonio Emanuele Di , Butterworth Adam S. , Danesh John , Samani Nilesh J. ,   for The UK Biobank CardioMetabolic Consortium CHD Working Group
Published: January 2018

AbstractBackgroundCoronary artery disease (CAD) has substantial heritability and a polygenic architecture; however, genomic risk scores have not yet leveraged the totality of genetic information available nor been externally tested at population-scale to show potential utility in primary prevention.MethodsUsing a meta-analytic approach to combine large-scale genome-wide and targeted genetic association data, we developed a new genomic risk score for CAD (metaGRS), consisting of 1.7 million genetic variants. We externally tested metaGRS, individually and in combination with available conventional risk factors, in 22,242 CAD cases and 460,387 non-cases from UK Biobank.FindingsIn UK Biobank, a standard deviation increase in metaGRS had a hazard ratio (HR) of 1.71 (95% CI 1.68–1.73) for CAD, greater than any other externally tested genetic risk score. Individuals in the top 20% of the metaGRS distribution had a HR of 4.17 (95% CI 3.97–4.38) compared with those in the bottom 20%. The metaGRS had higher C-index (C=0.623, 95% CI 0.615–0.631) for incident CAD than any of four conventional factors (smoking, diabetes, hypertension, and body mass index), and addition of the metaGRS to a model of conventional risk factors increased C-index by 3.7%. In individuals on lipid-lowering or anti-hypertensive medications at recruitment, metaGRS hazard for incident CAD was significantly but only partially attenuated with HR of 2.83 (95% CI 2.61– 3.07) between the top and bottom 20% of the metaGRS distribution.InterpretationRecent genetic association studies have yielded enough information to meaningfully stratify individuals using the metaGRS for CAD risk in both early and later life, thus enabling targeted primary intervention in combination with conventional risk factors. The metaGRS effect was partially attenuated by lipid and blood pressure-lowering medication, however other prevention strategies will be required to fully benefit from earlier genomic risk stratification.FundingNational Health and Medical Research Council of Australia, British Heart Foundation, Australian Heart Foundation.
Expression ofSULTR2;2in the Arabidopsis bundle sheath is mediated by a highly conserved positive regulator
Authors: Kirschner Sandra , Woodfield Helen , Prusko Katharina , Koczor Maria , Gowik Udo , Hibberd Julian M. , Westhoff Peter 
Published: January 2018

AbstractThe bundle sheath provides a conduit linking veins and mesophyll cells. In C3Arabidopsis thalianait also plays important roles in oxidative stress and sulphur metabolism. However, the mechanisms responsible for the patterns of gene expression that underpin these metabolic specialisations are poorly understood. Here we used theA. thaliana SULTR2;2gene as a model to better understand mechanisms that restrict expression to the bundle sheath. Deletion analysis indicated that theSULTR2;2promoter contains a short region necessary for expression in the bundle sheath. This sequence acts as a positive regulator and is tolerant to multiple consecutive deletions indicating considerable redundancy in thecis-elements involved. It is highly conserved inSULTR2;2genes of the Brassicaceae and is functional in the distantly related C4speciesFlaveria bidentisthat belongs to the Asteraceae. We conclude that expression ofSULTR2;2in the bundle sheath is underpinned by a highly redundant sequence that likely represents an ancient and conserved mechanism found in families as diverse as the Asteraceae and Brassicaceae.
Fine-tuning of substrate preferences of the Src-family kinase Lck revealed through a high-throughput specificity screen
Authors: Shah Neel H. , Löbel Mark , Weiss Arthur , Kuriyan John 
Published: January 2018

AbstractTo obtain a comprehensive map of the intrinsic specificities of tyrosine kinase domains, we developed a high-throughput method that uses bacterial surface-display and next-generation sequencing to analyze the specificity of any tyrosine kinase against a library of thousands of peptides derived from human tyrosine phosphorylation sites. Using this approach, we identified a difference in the electrostatic recognition of substrates between the cytoplasmic Src-family tyrosine kinases Lck and c-Src. This divergence likely reflects the specialization of Lck to act in concert with the tyrosine kinase ZAP-70 in T cell receptor signaling. The current understanding of substrate recognition by tyrosine kinases emphasizes the role of localization by non-catalytic domains, but our results point to the importance of direct recognition at the kinase active site in fine-tuning specificity. Our method provides a simple approach that leverages next-generation sequencing to readily map the specificity of any tyrosine kinase at the proteome level.
Conserved and ubiquitous expression of piRNAs and PIWI genes in mollusks antedates the origin of somatic PIWI/piRNA expression to the root of bilaterians
Authors: Jehn Julia , Gebert Daniel , Pipilescu Frank , Stern Sarah , Kiefer Julian Simon Thilo , Hewel Charlotte , Rosenkranz David 
Published: January 2018

AbstractPIWI proteins and a specific class of small non-coding RNAs, termed Piwi interacting RNAs (piRNAs), suppress transposon activity in animals on the transcriptional and post-transcriptional level, thus protecting genomes from detrimental insertion mutagenesis. While in vertebrates the PIWI/piRNA system appears to be restricted to the germline, somatic expression of piRNAs directed against transposons is widespread in arthropods, likely representing the ancestral state for this phylum. Here, we show that somatic expression of PIWI genes and piRNAs directed against transposons is conserved in mollusks, suggesting that somatic PIWI/piRNA expression was already realized in an early bilaterian ancestor. We further describe lineage specific adaptations regarding transposon composition of piRNA clusters and show that different piRNA clusters are dynamically expressed during oyster development. Finally, bioinformatics analyses suggest that different populations of piRNAs participate in the ping-pong amplification loop in a tissue specific manner.
Identification of rare de novo epigenetic variations in congenital disorders
Authors: Barbosa Mafalda , Joshi Ricky S. , Garg Paras , Martin-Trujillo Alejandro , Patel Nihir , Jadhav Bharati , Watson Corey T. , Gibson William , Chetnik Kelsey , Tessereau Chloe , Mei Hui , Rubeis Silvia De , Reichert Jennifer , Lopes Fatima , Vissers Lisenka E.L.M. , Kleefstra Tjitske , Grice Dorothy E. , Edelmann Lisa , Soares Gabriela , Maciel Patricia , Brunner Han G. , Buxbaum Joseph D. , Gelb Bruce D. , Sharp Andrew J. 
Published: January 2018

AbstractCertain human traits such as neurodevelopmental disorders (NDs) and congenital anomalies (CAs) are believed to be primarily genetic in origin. With recent dramatic advances in genomic technologies, genome-wide surveys of cohorts of patients with ND/CAs for point mutations and structural variations have greatly advanced our understanding of their genetic etiologies1,2. However, even after whole genome sequencing (WGS), a substantial fraction of such disorders remain unexplained3. In contrast, the possibility that constitutive epigenetic variations (epivariations) might underlie such traits has not been well explored. We hypothesized that some cases of ND/CA are caused by aberrations of DNA methylation that lead to a dysregulation of normal genome function. By comparing DNA methylation profiles from 489 individuals with ND/CAs against 1,534 population controls, we identified epivariations as a frequent occurrence in the human genome. De novo epivariations were significantly enriched in cases when compared to controls. RNAseq data from population studies showed that epivariations often have an impact on gene expression comparable to loss-of-function mutations. Additionally, we detected and replicated an enrichment of rare sequence mutations overlapping CTCF binding sites close to epivariations. Thus, some epivariations occur secondary to cis-linked mutations in regulatory regions, providing a rationale for interpreting non-coding genetic variation. We propose that epivariations likely represent the causative genomic defect in 5-10% of patients with unexplained ND/CAs. This constitutes a yield comparable to CNV microarrays, and as such has significant diagnostic relevance.
AlphaMate: a program for optimising selection, maintenance of diversity, and mate allocation in breeding programs
Authors: Gorjanc Gregor , Hickey John M. 
Published: January 2018

ABSTRACTSummaryAlphaMate is a flexible program that optimises selection, maintenance of genetic diversity, and mate allocation in breeding programs. It can be used in animal and cross- and self-pollinating plant populations. These populations can be subject to selective breeding or conservation management. The problem is formulated as a multi-objective optimisation of a valid mating plan that is solved with an evolutionary algorithm. A valid mating plan is defined by a combination of mating constraints (the number of matings, the maximal number of parents, the minimal/equal/maximal number of contributions per parent, or allowance for selfing) that are gender specific or generic. The optimisation can maximize genetic gain, minimize group coancestry, minimize inbreeding of individual matings, or maximize genetic gain for a given increase in group coancestry or inbreeding. Users provide a list of candidate individuals with associated gender and selection criteria information (if applicable) and coancestry matrix. Selection criteria and coancestry matrix can be based on pedigree or genome-wide markers. Additional individual or mating specific information can be included to enrich optimisation objectives. An example of rapid recurrent genomic selection in wheat demonstrates how AlphaMate can double the efficiency of converting genetic diversity into genetic gain compared to truncation selection. Another example demonstrates the use of genome editing to expand the gain-diversity frontier.AvailabilityExecutable versions of AlphaMate for Windows, Mac, and Linux platforms are available at http://www.alpha-genes.roslin.ed.ac.uk/AlphaMateContactgregor.gorjanc@roslin.ed.ack.uk
Low spatial structure and selection against secreted virulence factors attenuates pathogenicity inPseudomonas aeruginosa
Authors: Granato Elisa T. , Ziegenhain Christoph , Marvig Rasmus L. , Kümmerli Rolf 
Published: January 2018

ABSTRACTBacterial opportunistic pathogens are feared for their difficult-to-treat nosocomial infections and for causing morbidity in immunocompromised patients. Here, we study how such a versatile opportunist,Pseudomonas aeruginosa, adapts to conditions inside and outside its model hostCaenorhabditis elegans, and use phenotypic and genotypic screens to identify the mechanistic basis of virulence evolution. We found that virulence significantly dropped in unstructured environments both in the presence and absence of the host, but remained unchanged in spatially structured environments. Reduction of virulence was either driven by a substantial decline in the production of siderophores (in treatments without hosts) or toxins and proteases (in treatments with hosts). Whole-genome sequencing of evolved clones revealed positive selection and parallel evolution across replicates, and showed an accumulation of mutations in regulator genes controlling virulence factor expression. Our study identifies the spatial structure of the non-host environment as a key driver of virulence evolution in an opportunistic pathogen.
The genetics of behavioral isolation in an island system
Authors: Blankers Thomas , Oh Kevin P. , Shaw Kerry L. 
Published: January 2018

AbstractMating behavior divergence can make significant contributions to reproductive isolation and speciation in various biogeographic contexts. However, whether the genetic architecture underlying mating behavior divergence is related to the biogeographic history and the tempo and mode of speciation remains poorly understood. Here, we use quantitative trait locus (QTL) mapping to infer the number, distribution, and effect size of mating song rhythm variation in the cricketsLaupala eukoleaandL. cerasina, which occur on different islands (Maui and Hawai’i). We then compare these results with a similar study of an independently evolving species pair that diverged within the same island. Finally, we annotate theL. cerasinatranscriptome and test whether QTL fall in functionally enriched genomic regions. We document a polygenic architecture behind song rhythm divergence in the inter-island species pair that is remarkably similar to that previously found for an intra-island species pair in the same genus. Importantly, QTL regions were significantly enriched for potential homologs of genes involved in pathways that may be modulating cricket song rhythm. These clusters of loci could constrain the spatial genomic distribution of genetic variation underlying cricket song variation and harbor several candidate genes that merit further study.
RNA polymerase II pausing regulates a quiescence-dependent transcriptional program, priming cells for cell cycle reentry
Authors: Gala Hardik P. , Saha Debarya , Venugopal Nisha , Aloysius Ajoy , Dhawan Jyotsna 
Published: January 2018

AbstractAdult stem cells persist in mammalian tissues by entering a state of reversible arrest or quiescence associated with low transcription. Using cultured myoblasts and primary muscle stem cells, we show that RNA synthesis is strongly repressed in G0, returning within minutes of activation. We investigate the underlying mechanism and reveal a role for promoter-proximal RNAPol II pausing: by mapping global Pol II occupancy using ChIP-seq, in conjunction with RNA-seq to identify repressed transcriptional networks unique to G0. Strikingly, Pol II pausing is enhanced in G0on genes encoding regulators of RNA biogenesis (Ncl, Rps24, Ctdp1), and release of pausing is critical for cell cycle re-entry. Finally, we uncover a novel, unexpected repressive role of the super-elongation complex component Aff4 in G0-specific stalling. We propose a model wherein Pol II pausing restrains transcription to maintain G0, preconfigures gene networks required for the G0-G1transition, and sets the timing of their transcriptional activation.
HIF-2α is essential for carotid body development and function
Authors: Macías David , Cowburn Andrew S. , Torres-Torrelo Hortensia , Ortega-Sáenz Patricia , López-Barneo José , S. Johnson Randall 
Published: January 2018

SummaryMammalian adaptation to oxygen flux occurs at many levels, from shifts in cellular metabolism to physiological adaptations facilitated by the sympathetic nervous system and carotid body (CB). Interactions between differing forms of adaptive response to hypoxia, including transcriptional responses orchestrated by the Hypoxia Inducible transcription Factors (HIFs), are complex and clearly synergistic. We show here that there is an absolute developmental requirement for HIF-2a, one of the HIF isoforms, for growth and survival of oxygen sensitive glomus cells of the carotid body. The loss of these cells renders mice incapable of ventilatory responses to hypoxia, and this has striking effects on processes as diverse as arterial pressure regulation, exercise performance, and glucose homeostasis. We show that the expansion of the glomus cells is correlated with mTORC1 activation, and is functionally inhibited by rapamycin treatment. These findings demonstrate the central role played by HIF-2a in carotid body development, growth and function.