bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Symmetric Prior for the Regularisation of Elastic Deformations: Improved Anatomical Plausibility in Nonlinear Image Registration
Authors: Lange Frederik J , Ashburner John , Smith Stephen M , Andersson Jesper L R 
Published: June 2019

AbstractNonlinear registration is critical to many aspects of Neuroimaging research. It facilitates averaging and comparisons across multiple subjects, as well as reporting of data in a common anatomical frame of reference. It is, however, a fundamentally ill-posed problem, with many possible solutions which minimise a given dissimilarity metric equally well. We present a novel regularisation method that aims to selectively drive solutions towards those which would be considered anatomically plausible by penalising unlikely lineal, areal and volumetric deformations. In addition, our penalty is symmetric in the sense that geometric expansions and contractions are penalised equally, which encourages inverse-consistency. We demonstrate that our method is able to significantly reduce volume and shape distortions compared to state-of-the-art elastic (FNIRT) and plastic (ANTs) registration frameworks. Crucially, this is achieved whilst matching or exceeding the registration quality of these methods, as measured by overlap scores of labelled cortical regions. Furthermore, extensive use of GPU parallelisation has allowed us to implement what is a highly computationally intensive optimisation strategy while maintaining reasonable run times of under half an hour.
The effect of sex and underlying disease on the genetic association of QT interval and sudden cardiac death
Authors: Mitchell Rebecca N. , Ashar Foram N. , Jarvelin Marjo-Riitta , Froguel Philippe , Sotoodehnia Nona , Brody Jennifer A. , Sebert Sylvain , Huikuri Heikki , Rioux John , Goyette Philippe , Newcomb Charles E. , Junttila M. Juhani , Arking Dan E. 
Published: June 2019

ABSTRACTBackgroundSudden cardiac death (SCD) accounts for ~300,000 deaths annually in the US. Men have a higher risk of SCD and are more likely to have underlying coronary artery disease (CAD) than women. In contrast, women are more likely to have arrhythmic events in the setting of inherited or acquired QT prolongation. Moreover, there is evidence of sex differences in the underlying genetics of QT interval duration. Using sex- and CAD-stratified analyses, we assess differences in genetic association between prolonged QT interval and SCD risk.MethodsWe examined 2,282 SCD subjects with autopsy-confirmed underlying disease from the Fingesture cohort and 3,561 Finnish controls. The SCD subjects were stratified by underlying disease (ischemic vs. non-ischemic) and by sex. We used logistic regression to test for association between the top QT interval associated SNP, rs12143842 (in the NOS1AP locus), and SCD risk. We also performed Mendelian randomization to test for causal association of QT interval in the various subgroups.ResultsFemale SCD victims with underlying non-ischemic disease had the strongest association between rs12143842 and SCD risk (OR=1.37; 95% CI, 1.07-1.75) and the strongest causal association, established using Mendelian randomization, between prolonged QT interval and SCD (OR in SCD risk per SD increase in QT, 3.60; 95% CI, 1.22-10.49). Ischemic SCD victims, irrespective of sex, did not show an association between rs12143842 and SCD risk or a causal association for QT interval.ConclusionsThis study provides evidence that the causal effect of QT prolongation on SCD risk differs by sex and underlying disease.
Artificial selection on male size depletes genetic variance but not covariance of life history traits in the yellow dung fly
Authors: Blanckenhorn WU , Llaurens V , Reim C , Teuschl Y , Postma E 
Published: June 2019

SUMMARYThe evolutionary potential of organisms depends on the presence of sufficient genetic variation for traits subject to selection, as well as on the genetic covariances among them. While genetic variation ultimately derives from mutation, theory predicts the depletion of genetic (co)variation under consistent directional or stabilizing selection in natural populations. We estimated and compared additive genetic (co)variances for several standard life history traits, including some for which this has never been assessed, before and after 24 generations of artificial selection on male size in the yellow dung flyScathophaga stercoraria(Diptera: Scathophagidae) using a series of standard half-sib breeding experiments. As predicted, genetic variances (VA), heritabilities (h2) and evolvabilities (IA) of body size, development time, first clutch size, and female age at first clutch were lower after selection. As independent selection lines were crossed prior to testing, we can rule out that this reduction is due to genetic drift. In contrast to the variances, and against expectation, the additive genetic correlations between the sexes for development time and body size remained strong and positive (rA =0.8–0.9), while the genetic correlation between these traits within the sexes tended to strengthen (but not significantly so). Our study documents that the effect of selection on genetic variance is predictable, whereas that on genetic correlations is not.
Rapid response to the Alpha-1 Adrenergic Agent Phenylephrine in the Perioperative Period is Impacted by Genomics and Ancestry
Authors: Wenric Stephane , Jeff Janina M. , Joseph Thomas , Yee Muh-Ching , Belbin Gillian M. ,   Regeneron Genetics Center,   CBIPM Genomics Group, Obeng Aniwaa Owusu , Ellis Stephen B. , Bottinger Erwin P. , Gottesman Omri , Levin Matthew A. , Kenny Eimear E. 
Published: June 2019

AbstractBackgroundThe emergence of genomic data in biobanks and health systems offers new ways to derive medically important phenotypes, including acute phenotypes that occur during in-patient clinical care. We hypothesized that there is a genetic underpinning to the magnitude of the response to phenylephrine, an α1-adrenergic receptor agonist commonly used to treat hypotension during anesthesia and surgery.MethodsWe quantified the response to phenylephrine by determining the delta between the minimum blood pressure (BP) within five minutes before and the maximum BP within five minutes after bolus administration. We then performed a genome-wide association study (GWAS) adjusted for genetic ancestry, demographics, and relevant clinical covariates to investigate genetic factors underlying individual differences systolic BP response to phenylephrine (ΔSBP), as well as mean arterial pressure (ΔMAP) and diastolic BP (ΔDBP), for both the entire study cohort as well as for each of 3 ancestry sub-cohorts; European American(EA), African American(AA), and Hispanic American(HA).Results4,317 patients met inclusion criteria, of which 3,699 were genotyped. Average ΔBP values over the entire cohort were ΔSBP=17(+-25) mmHg, ΔMAP=14(+-18) mmHg, ΔDBP=11(+-14) mmHg. The largest difference between populations was observed for ΔSBP (ΔSBPEA=20(+-24) mmHg; ΔSBPHA=16(+-25) mmHg; ΔSBPAA=15(+-25) mmHg). The differences remained after adjusting for clinical covariates and ancestry (EA vs. HA: ΔSBP, p<0.032;ΔMAP, p<0.021;ΔDBP,p<0.008);(EA vs. AA:ΔSBP,p<5.13×10-5;ΔMAP,p<2.1×10-4;ΔDBP,p<3.3×10-4). GWAS revealed significant associations between loci and BP response in 5 different genome regions (p<5×10-8) in the entire cohort, and suggestive associations in 2 different regions in EAs (p<6×10-8,p<7×10-8). We observed non-random enrichment in association with SBP drug response in 165 loci previously reported to be associated with systolic blood pressure. Finally, we discovered rare variants, rs188427942 and rs147664194 present at ∼1% in EAs and rs146535276 present at ∼1% in AAs respectively, where patients carrying one copy of these variants show no response to phenylephrine.ConclusionsIt is possible to derive a quantitative phenotype suited for comparative statistics and genome-wide association studies from routinely collected perioperative data. There are population differences in rapid response to phenylephrine, large effect alleles and novel genes affecting pharmaceutical response, and phenylephrine non-responders, with implications for personalized treatment during surgery.
Anatomical meniscus construct with zone specific biochemical composition and structural organization
Authors: Bahcecioglu G. , Bilgen B. , Hasirci N. , Hasirci V. 
Published: June 2019

AbstractA PCL/hydrogel construct that would mimic the structural organization, biochemistry and anatomy of meniscus was engineered. The compressive (380 ± 40 kPa) and tensile modulus (18.2 ± 0.9 MPa) of the PCL scaffolds were increased significantly when constructs were printed with a shifted design and circumferential strands mimicking the collagen organization in native tissue (p<0.05). Presence of circumferentially aligned PCL strands also led to elongation and alignment of the human fibrochondrocytes. Gene expression of the cells in agarose (Ag), gelatin methacrylate (GelMA), and GelMA-Ag hydrogels was significantly higher than that of cells on the PCL scaffolds after a 21-day culture. GelMA exhibited the highest level of collagen type I (COL1A2)mRNA expression, while GelMA-Ag exhibited the highest level of aggrecan (AGG)expression (p<0.001, compared to PCL). GelMA and GelMA-Ag exhibited a high level of collagen type II (COL2A1) expression (p<0.05, compared to PCL). Anatomical scaffolds with circumferential PCL strands were impregnated with cell-loaded GelMA in the periphery and GelMA-Ag in the inner region. GelMA and GelMA-Ag hydrogels enhanced the production of COL 1 and COL 2 proteins after a 6-week culture (p<0.05). COL 1 expression increased gradually towards the outer periphery, while COL 2 expression decreased. We were thus able to engineer an anatomical meniscus with a cartilage-like inner region and fibrocartilage-like outer region.
An ultra high-densityArabidopsis thalianacrossover map that refines the influences of structural variation and epigenetic features
Authors: Rowan Beth A. , Heavens Darren , Feuerborn Tatiana R. , Tock Andrew J. , Henderson Ian R. , Weigel Detlef 
Published: June 2019

AbstractMany environmental, genetic, and epigenetic factors are known to affect the frequency and positioning of meiotic crossovers (COs). Suppression of COs by large, cytologically visible inversions and translocations has long been recognized, but relatively little is known about how smaller structural variants (SVs) affect COs. To examine fine-scale determinants of the CO landscape, including SVs, we used a rapid, cost-effective method for high-throughput sequencing to generate a precise map of over 17,000 COs between the Col-0 and Ler accessions ofArabidopsis thaliana. COs were generally suppressed in regions with SVs, but this effect did not depend on the size of the variant region, and was only marginally affected by the variant type. CO suppression did not extend far beyond the SV borders, and CO rates were slightly elevated in the flanking regions. Disease resistance gene clusters, which often exist as SVs, exhibited high CO rates at some loci, but there was a tendency toward depressed CO rates at loci where large structural differences exist between the two parents. Our high-density map also revealed in fine detail how CO positioning relates to genetic (DNA motifs) and epigenetic (chromatin structure) features of the genome. We conclude that suppression of COs occurs over a narrow region spanning large and small-scale SVs, representing influence on the CO landscape in addition to sequence and epigenetic variation along chromosomes.
Type-2-diabetes Alters CSF but not Plasma Metabolomic and AD Risk Profiles in Vervet Monkeys
Authors: Kavanagh Kylie , Day Stephen M. , Pait Morgan C. , Mortiz William R. , Newgard Christopher B. , Ilkayeva Olga , Mcclain Donald A. , Macauley Shannon L. 
Published: June 2019

AbstractEpidemiological studies suggest that individuals with type 2 diabetes (T2D) have a 2-4 fold increased risk for developing Alzheimer’s disease (AD), however the exact mechanisms linking the two disease is unknown. In both conditions, the majority of pathophysiological changes (including glucose and insulin dysregulation, insulin resistance, and AD-related changes in Aβ and tau) occur decades before the onset of clinical symptoms and diagnosis. In this study, we investigated the relationship between metabolic biomarkers associated with T2D and AD-related pathology, including Aβ levels, from cerebrospinal fluid (CSF) and fasting plasma of healthy, prediabetic (PreD), and T2D vervet monkeys (Chlorocebus aethiops sabeus). Consistent with the human disease, T2D monkeys have increased plasma and CSF glucose levels as they transition from normoglycemia to pre-diabetic and diabetic states. Although plasma levels of acylcarnitines and amino acids remained largely unchanged, peripheral hyperglycemia correlated with decreased CSF acylcarnitines and CSF amino acids, including branched chain amino acid (BCAA) concentrations, suggesting profound changes in cerebral metabolism coincident with systemic glucose dysregulation. Moreover, CSF Aβ40 and CSF Aβ42 levels decreased in T2D monkeys, a phenomenon observed in the human course of AD which coincides with increased amyloid deposition within the brain. In agreement with our previous studies in mice, CSF Aβ40 and CSF Aβ42 were highly correlated with CSF glucose levels, suggesting that glucose levels in the brain are associated with changes in Aβ metabolism. Interestingly, CSF Aβ40 and CSF Aβ42 levels were also highly correlated with plasma but not CSF lactate levels, suggesting that plasma lactate might serve as a potential biomarker of disease progression in AD. Moreover, CSF glucose and plasma lactate levels were correlated with CSF amino acid and acylcarnitine levels, demonstrating alterations in cerebral metabolism occurring with the onset of T2D. Together, these data suggest that peripheral metabolic changes associated with the development of T2D produce alterations in brain metabolism that lead to early changes in the amyloid cascade, similar to those observed in pre-symptomatic AD.
Why evolve reliance on the microbiome for timing of ontogeny?
Authors: Metcalf C. Jessica E. , Henry Lucas P. , Rebolleda-Gómez María , Koskella Britt 
Published: June 2019

AbstractThe timing of life history events has important fitness consequences. Since the 1950s, researchers have combined first principles and data to predict the optimal timing of life history transitions. Recently, a striking mystery has emerged. Such transitions can be shaped by a completely different branch of the tree of life: bacterial species in the microbiome. Probing these interactions using testable predictions from evolutionary theory could illuminate whether and how host-microbiome integrated life histories can evolve and be maintained. Beyond advancing fundamental science, this research program could yield important applications. In an age of microbiome engineering, understanding the contexts that lead to microbiota signaling shaping ontogeny could offer novel mechanisms for manipulations to increase yield in agriculture, or reduce pathogen transmission by affecting vector efficiency. We combine theory and evidence to illuminate the essential questions underlying the existence ofMicrobiomeDependentOntogeneticTiming (MiDOT) to fuel research on this emerging topic.
Neuronal TORC1 modulates longevity via AMPK and cell nonautonomous regulation of mitochondrial dynamics inC. elegans
Authors: Zhang Yue , Lanjuin Anne , Chowdhury Suvagata Roy , Mistry Meeta , Silva Garcia Carlos G. , Weir Heather J. , Lee Chia-Lin , Escoubas Caroline C. , Tabakovic Emina , Mair William B. 
Published: June 2019

AbstractTarget of rapamycin complex 1 (TORC1) and AMP-activated protein kinase (AMPK) antagonistically modulate metabolism and aging. However, how they coordinate to determine longevity and if they act via separable mechanisms is unclear. Here, we show that neuronal AMPK is essential for lifespan extension from TORC1 inhibition, and that TORC1 suppression increases lifespan cell non autonomously via distinct mechanisms from global AMPK activation. Lifespan extension by null mutations in genes encodingraga-1(RagA) orrsks-1(S6K) is fully suppressed by neuronal-specific rescues. Loss of RAGA-1 increases lifespan via maintaining mitochondrial fusion. Neuronal RAGA-1 abrogation ofraga-1mutant longevity requires UNC-64/syntaxin, and promotes mitochondrial fission cell nonautonomously. Finally, deleting the mitochondrial fission factor DRP-1 renders the animal refractory to the pro-aging effects of neuronal RAGA-1. Our results highlight a new role for neuronal TORC1 in cell nonautonomous regulation of longevity, and suggest TORC1 in the central nervous system might be targeted to promote healthy aging.
Multiplex chromatin interaction analysis by signal processing and statistical algorithms
Authors: Kim Minji , Zheng Meizhen , Tian Simon Zhongyuan , Capurso Daniel , Lee Byoungkoo , Chuang Jeffrey H. , Ruan Yijun 
Published: June 2019

AbstractThe single-molecule multiplex chromatin interaction data generated by emerging non-ligation-based 3D genome mapping technologies provide novel insights into high dimensional chromatin organization, yet introduce new computational challenges. We developed MIA-Sig (https://github.com/TheJacksonLaboratory/mia-sig.git), an algorithmic framework to de-noise the data, assess the statistical significance of chromatin complexes, and identify topological domains and inter-domain contacts. On chromatin immunoprecipitation (ChIP)-enriched data, MIA-Sig can clearly distinguish the protein-associated interactions from the non-specific topological domains.
A burst of genetic innovation in actin-related proteins (Arps) for testis-specific function in aDrosophilalineage
Authors: Schroeder Courtney M. , Valenzuela John , Hocky Glen M. , Malik Harmit S. 
Published: June 2019

AbstractMany cytoskeletal proteins form the core of fundamental biological processes and are evolutionarily ancient. For example, the superfamily of actin-related proteins (Arps) specialized early in eukaryotic evolution for diverse cellular roles in the cytoplasm and the nucleus. Despite its strict conservation across eukaryotes, we find that the Arp superfamily has undergone dramatic lineage-specific diversification inDrosophila. Our phylogenomic analyses reveal four independent Arp gene duplications that originated in the common ancestor of theobscuragroup ofDrosophilaspecies and have been mostly preserved in this lineage. All four Arp paralogs have evolved under positive selection and are predominantly expressed in the male germline. We focus our analyses on the divergentArp2Dparalog, which arose via a retroduplication event fromArp2, a component of the 7-membered Arp2/3 complex that polymerizes branched actin networks. Computational modeling analyses suggest that Arp2D should be able to replace Arp2 in the Arp2/3 complex and bind daughter actin monomers, suggesting that Arp2D may augment Arp2’s functions in the male germline. We find that Arp2D is expressed during and following meiosis in the male germline, where it localizes to distinct locations such as actin cones–pecialized cytoskeletal structures that separate bundled spermatids into individual mature sperm. We hypothesize that this unprecedented burst of genetic innovation in cytoskeletal proteins may have been driven by the evolution of sperm heteromorphism in theobscuragroup ofDrosophila.
Single-cell proteomic and transcriptomic analysis of macrophage heterogeneity
Authors: Specht Harrison , Emmott Edward , Petelski Aleksandra A. , Huffman R. Gray , Perlman David H. , Serra Marco , Kharchenko Peter , Koller Antonius , Slavov Nikolai 
Published: June 2019

AbstractMacrophages are innate immune cells with diverse functional and molecular phenotypes. This diversity is largely unexplored at the level of single-cell proteomes because of limitations of quantitative single-cell protein analysis. To overcome this limitation, we developed SCoPE2, which substantially increases quantitative accuracy and throughput while lowering cost and hands-on time by introducing automated and miniaturized sample preparation. These advances enable us to analyze the emergence of cellular heterogeneity as homogeneous monocytes differentiate into macrophage-like cells in the absence of polarizing cytokines. SCoPE2 quantified over 3,042 proteins in 1,490 single monocytes and macrophages in ten days of instrument time, and the quantified proteins allow us to discern single cells by cell type. Furthermore, the data uncover a continuous gradient of proteome states for the macrophages, suggesting that macrophage heterogeneity may emerge in the absence of polarizing cytokines. This gradient correlates to the inflammatory axis of classically and alternatively activated macrophages. Parallel measurements of transcripts by 10x Genomics suggest that our measurements sample 20-fold more protein copies than RNA copies per gene, and thus SCoPE2 supports quantification with improved count statistics. The joint distributions of proteins and transcripts allowed exploring regulatory interactions, such as between the tumor suppressor p53, its transcript, and the transcripts of genes regulated by p53. Our methodology lays the foundation for quantitative single-cell analysis of proteins by mass-spectrometry and demonstrates the potential for inferring transcriptional and post-transcriptional regulation from variability across single cells.Abstract Figure
Dynamics of Meiotic Sex Chromosome Inactivation and Pachytene Activation in Mice Spermatogenesis
Authors: Vértesy Ábel , Frias-Aldeguer Javier , Sahin Zeliha , Rivron Nicolas , van Oudenaarden Alexander , Geijsen Niels 
Published: June 2019

AbstractDuring germ cell development, cells undergo a drastic switch from mitosis to meiosis to form haploid germ cells. Sequencing and computational technologies now allow studying development at the single-cell level. Here we developed a multiplexed trajectory reconstruction to create a high-resolution developmental map of spermatogonia and prophase-I spermatocytes from testes of a Dazl-GFP reporter mouse. We identified three main transitions in the meiotic prophase-I: meiotic entry, the meiotic sex chromosome inactivation (MSCI), and concomitant pachytene activation. We validated the key features of these transitionsin vivousing single molecule FISH. Focusing on MSCI, we found that 34% of sex chromosomal genes are induced shortly before MSCI, that silencing time is diverse and correlates with specific gene functions. These highlight a previously underappreciated level of regulation of MSCI. Finally, we found that spermatozoal genes in pachytene are activated in a temporal pattern reflecting the future anatomic and functional order of the sperm cell. Altogether we highlighted how precise and sequential changes in gene expression regulate cellular states in meiotic prophase-I.