bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin-6 Promotes Murine Estrogen Deficiency-Associated Cerebral Aneurysm Rupture
Authors: Wajima Daisuke , Hourani Siham , Dodd William , Patel Devan , Jones Chad , Motwani Kartik , Fazal Hanain Z , Hosaka Koji , Hoh Brian L 
Published: June 2019

Abstract

BACKGROUND
Estrogen deficiency is associated with cerebral aneurysm rupture, but the precise mechanism is unknown.

OBJECTIVE
To test the hypothesis that IL-6 is required for the increase in aneurysm rupture rate observed in estrogen-deficient mice.

METHODS
We analyzed IL-6 expression in human cerebral aneurysms. We induced cerebral aneurysms in estrogen-deficient female C57BL/6 mice that had undergone 4-vinylcyclohexene diepoxide (VCD) treatment or bilateral ovariectomy (OVE). Mice were blindly randomized to selective IL-6 inhibition (IL-6 receptor [IL-6R] neutralizing antibody, n = 25) or control (isotype-matched IgG, n = 28). Murine cerebral arteries at the circle of Willis were assessed for aneurysm rupture and macrophage infiltration.

RESULTS
IL-6 is expressed in human cerebral aneurysms, but not in control arteries. Serum IL-6 is elevated in ovariectomized female mice compared to sham control (14.3 ± 1.7 pg/mL vs 7.4 ± 1.5 pg/mL, P = .008). Selective IL-6R inhibition suppressed cerebral aneurysm rupture in estrogen-deficient mice compared with control (VCD: 31.6% vs 70.0%, P = .026; OVE: 28.6% vs 65.2%, P = .019). IL-6R inhibition had no effect on formation or rupture rate in wild-type mice. IL-6R neutralizing antibody significantly reduced macrophage infiltration at the circle of Willis (1.9 ± 0.2 vs 5.7 ± 0.6 cells/2500 μm2; n = 8 vs n = 15; P < .001).

CONCLUSION
IL-6 is increased in the serum of estrogen-deficient mice and appears to play a role in promoting murine estrogen deficiency-associated cerebral aneurysm rupture via enhanced macrophage infiltration at the circle of Willis. Inhibition of IL-6 signaling via IL-6 receptor neutralizing antibody inhibits aneurysm rupture in estrogen-deficient mice. IL-6 receptor inhibition had no effect on aneurysm formation or rupture in wild-type animals.
Why Spirituality Matters for Law: An Explanation
Authors: Domingo Rafael 
Published: June 2019

Abstract
In this article, I explore potential connections between law and spirituality as well as some of the legal implications of these connections. After arguing that spirituality is conceptually autonomous from religion and morality, I explain why the spiritual triad of love, communion, and gift is deeply interconnected with the legal triad of justice, agreement, and right. I also make clear why individual and collective intentions and cultural values are the main channels of interaction between law and spirituality. In the second part of the article, I argue that legal systems evolve through spiritualization, among other ways, promoting the dematerialization of the legal system, encouraging the limitation of domination, inspiring the reduction of coercion, stimulating communion and consensus in society, or increasing respect for the law and the legal systems. Spiritualization demands a recognition of the higher dimension of the law and, therefore, helps rethink, reorient, renew, reform, and reimagine law and legal systems. Finally, I sketch a pattern of five levels to measure the degree of spiritualization of concrete legal systems. This pattern can also be applied to legal actors and institutions.
Phylogenomics Uncovers Confidence and Conflict in the Rapid Radiation of Australo-Papuan Rodents
Authors: Roycroft Emily J , Moussalli Adnan , Rowe Kevin C 
Published: June 2019

Abstract
The estimation of robust and accurate measures of branch support has proven challenging in the era of phylogenomics. In data sets of potentially millions of sites, bootstrap support for bifurcating relationships around very short internal branches can be inappropriately inflated. Such overestimation of branch support may be particularly problematic in rapid radiations, where phylogenetic signal is low and incomplete lineage sorting severe. Here, we explore this issue by comparing various branch support estimates under both concatenated and coalescent frameworks, in the recent radiation Australo-Papuan murine rodents (Muridae: Hydromyini). Using nucleotide sequence data from 1245 independent loci and several phylogenomic inference methods, we unequivocally resolve the majority of genus-level relationships within Hydromyini. However, at four nodes we recover inconsistency in branch support estimates both within and among concatenated and coalescent approaches. In most cases, concatenated likelihood approaches using standard fast bootstrap algorithms did not detect any uncertainty at these four nodes, regardless of partitioning strategy. However, we found this could be overcome with two-stage resampling, that is, across genes and sites within genes (using -bsam GENESITE in IQ-TREE). In addition, low confidence at recalcitrant nodes was recovered using UFBoot2, a recent revision to the bootstrap protocol in IQ-TREE, but this depended on partitioning strategy. Summary coalescent approaches also failed to detect uncertainty under some circumstances. For each of four recalcitrant nodes, an equivalent (or close to equivalent) number of genes were in strong support ($&gt;$ 75% bootstrap) of both the primary and at least one alternative topological hypothesis, suggesting notable phylogenetic conflict among loci not detected using some standard branch support metrics. Recent debate has focused on the appropriateness of concatenated versus multigenealogical approaches to resolving species relationships, but less so on accurately estimating uncertainty in large data sets. Our results demonstrate the importance of employing multiple approaches when assessing confidence and highlight the need for greater attention to the development of robust measures of uncertainty in the era of phylogenomics.
Activation of MAIT cells plays a critical role in viral vector vaccine immunogenicity
Authors: Provine Nicholas M. , Amini Ali , Garner Lucy C. , Dold Christina , Hutchings Claire , FitzPatrick Michael E.B. , Reyes Laura Silva , Chinnakannan Senthil , Oguti Blanche , Raymond Meriel , Capone Stefania , Folgori Antonella , Rollier Christine S. , Barnes Eleanor , Pollard Andrew J. , Klenerman Paul 
Published: June 2019

AbstractMucosal-associated invariant T (MAIT) cells can be activated by viruses through a cytokine-dependent mechanism, and thereby protect from lethal infection. Given this, we reasoned MAIT cells may have a critical role in the immunogenicity of replication-incompetent adenovirus vectors, which are novel and highly potent vaccine platforms. In vitro, ChAdOx1 (Chimpanzee Adenovirus Ox1) induced potent activation of MAIT cells. Activation required transduction of monocytes and plasmacytoid dendritic cells to produce IL-18 and IFN-α, respectively. IFN-α-induced monocyte-derived TNF-α was identified as a novel intermediate in this activation pathway, and activation required combinatorial signaling of all three cytokines. Furthermore, ChAdOx1-induced in vivo MAIT cell activation in both mice and human volunteers. Strikingly, MAIT cell activation was necessary in vivo for development of ChAdOx1-induced HCV-specific CD8 T cell responses. These findings define a novel role for MAIT cells in the immunogenicity of viral vector vaccines, with potential implications for future design.One sentence summaryRobust immunogenicity of candidate adenovirus vaccine vectors requires the activation of unconventional T cells.
The genomic architecture of blood metabolites based on a decade of genome-wide analyses
Authors: Hagenbeek Fiona A. , Pool René , van Dongen Jenny , Draisma Harmen H.M. , Hottenga Jouke Jan , Willemsen Gonneke , Abdellaoui Abdel , Fedko Iryna O. , Braber Anouk den , Visser Pieter Jelle , de Geus Eco J.C.N. , van Dijk Ko Willems , Verhoeven Aswin , Suchiman H. Eka , Beekman Marian , Slagboom P. Eline , van Duijn Cornelia M. ,   BBMRI Metabolomics Consortium, Harms Amy C. , Hankemeier Thomas , Bartels Meike , Nivard Michel G. , Boomsma Dorret I. 
Published: June 2019

AbstractMetabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes and lipid species. We performed a review of all genetic association studies, and identified > 800 class-specific metabolite loci that influence metabolite levels. In a twin-family cohort (N= 5,117), these metabolite loci were leveraged to simultaneously estimate total heritability (h2total), and the proportion of heritability captured by known metabolite loci (h2Metabolite-hits) for 309 lipids and 52 organic acids. Our study revealed significant differences inh2Metabolite-hitsamong different classes of lipids and organic acids. Furthermore, phosphatidylcholines with a high degree of unsaturation had higherh2Metabolite-hitsestimates than phosphatidylcholines with a low degree of unsaturation. This study highlights the importance of common genetic variants for metabolite levels, and elucidates the genetic architecture of metabolite classes and lipid species.
Reconstruction of the carbohydrate 6-O sulfotransferase gene family evolution in vertebrates reveals novel member, CHST16, lost in amniotes
Authors: Ocampo Daza Daniel , Haitina Tatjana 
Published: June 2019

AbstractGlycosaminoglycans are sulfated polysaccharide molecules, essential for many biological processes. The 6-O sulfation of glycosaminoglycans is carried out by carbohydrate 6-O sulfotransferases (C6OST), previously named Gal/GalNAc/GlcNAc 6-O sulfotransferases. Here for the first time we present a detailed phylogenetic reconstruction, analysis of gene synteny conservation and propose an evolutionary scenario for the C6OST family in major vertebrate groups, including mammals, birds, non-avian reptiles, amphibians, lobe-finned fishes, ray-finned fishes, cartilaginous fishes and jawless vertebrates. The C6OST gene expansion likely occurred in the chordate lineage, after the divergence of tunicates and before the emergence of extant vertebrate lineages.The two rounds of whole genome duplication in early vertebrate evolution (1R/2R) only contributed two additional C6OST subtype genes, increasing the vertebrate repertoire from four genes to six, divided into two branches. The first branch includesCHST1andCHST3as well as a previously unrecognized subtype,CHST16, that was lost in amniotes. The second branch includesCHST2,CHST7andCHST5. Subsequently, local duplications ofCHST5gave rise toCHST4in the ancestor of tetrapods, and toCHST6in the ancestor of primates.The teleost specific gene duplicates were identified forCHST1,CHST2andCHST3and are result of whole genome duplication (3R) in the teleost lineage. We could also detect multiple, more recent lineage-specific duplicates. Thus, the repertoire of C6OST genes in vertebrate species has been shaped by different events at several stages during vertebrate evolution, with implications for the evolution of the skeleton, nervous system and cell-cell interactions.
Concise whole blood transcriptional signatures for incipient tuberculosis: A systematic review and patient-level pooled meta-analysis
Authors: Gupta Rishi K. , Turner Carolin T. , Venturini Cristina , Esmail Hanif , Rangaka Molebogeng X. , Copas Andrew , Lipman Marc , Abubakar Ibrahim , Noursadeghi Mahdad 
Published: June 2019

AbstractBlood transcriptional signatures may predict risk of tuberculosis (TB). We compared the performance of 17 mRNA signatures in a pooled dataset comprising 1,026 samples, including 183 samples from 127 incipient TB cases, from four studies conducted in South Africa, Ethiopia, The Gambia and the UK. We show that eight signatures (comprising 1-25 transcripts) that predominantly reflect interferon inducible gene expression, have equivalent diagnostic accuracy for incipient TB over a two-year period with areas under the receiver operating characteristic curves ranging from 0.70 (95% confidence interval 0.64-0.76) to 0.77 (0.71-0.82). The sensitivity of all eight signatures declined with increasing disease-free time interval. Using a threshold derived from two standard deviations above the mean of uninfected controls giving specificities of >90%, the eight signatures achieved sensitivities ranging 24.7-39.9% over a 24 month interval, rising to 47.1-81.0% over 3 months. Based on pre-test probability of 2%, the eight signatures achieved positive predictive value ranging from 6.8-9.4% over 24 months, rising to 11.1-14.3% over 3 months. When using biomarker thresholds maximising sensitivity and specificity with equal weighting to both, no signature met the minimum World Health Organization (WHO) Target Product Profile parameters for incipient TB biomarkers over a two-year period. Blood transcriptional biomarkers reflect short-term risk of TB and only exceed WHO benchmarks if applied to 3-6 month intervals.
Oscillatory Viscoelastic Microfluidics for Efficient Focusing and Separation of Nanoscale Species
Authors: Asghari Mohammad , Cao Xiaobao , Mateescu Bogdan , van Leeuwen Daniel , Stavrakis Stavros , deMello Andrew J. 
Published: June 2019

AbstractThe ability to precisely control particle migration within microfluidic systems is essential for focusing, separating, counting and detecting a wide range of biological species. To date, viscoelastic microfluidic systems have primarily been applied to the focusing, separation and isolation of micron-sized species, with their use in nanoparticle manipulations being underdeveloped and underexplored, due to issues related to nanoparticle diffusivity and a need for extended channel lengths. To overcome such issues, we herein present sheathless oscillatory viscoelastic microfluidics as a method for focusing and separating both micron and sub-micron species. To highlight the efficacy of our approach, we segment our study into three size regimes, namely micron (where characteristic particle dimensions are above 1 μm), sub-micron (where characteristic dimensions are between 1 μm and 100 nm) and nano (where characteristic dimensions are below 100 nm) regimes. Based on the ability to successfully manipulate particles in all these regimes, we demonstrate the successful isolation of p-bodies from biofluids (in the micron regime), the focusing of λ-DNA (in the sub-micron regime) and the focusing of extracellular vesicles (in the nano-regime). Finally, we characterize the physics underlying viscoelastic microflows using a dimensionless number that relates the lateral velocity (due to elastic effects) to the diffusion constant of the species within the viscoelastic carrier fluid. Based on the ability to precisely manipulate species in all three regimes, we expect that sheathless oscillatory viscoelastic microfluidics will provide for significant new opportunities in a range of biological and life science applications.
Humanization of yeast genes with multiple human orthologs reveals principles of functional divergence between paralogs
Authors: Laurent Jon M. , Garge Riddhiman K. , Teufel Ashley I. , Wilke Claus O. , Kachroo Aashiq H. , Marcotte Edward M. 
Published: June 2019

AbstractDespite over a billion years of evolutionary divergence, several thousand human genes possess clearly identifiable orthologs in yeast, and many have undergone lineage-specific duplications in one or both lineages. The ortholog conjecture postulates that orthologous genes between species retain ancestral functions despite divergence over vast timescales, but duplicated genes will be free to diverge in function. However, the retention of ancestral functions among co-orthologs between species and within gene families has been difficult to test experimentally at scale. In order to investigate how ancestral functions are retained or lost post-duplication, we systematically replaced hundreds of essential yeast genes with their human orthologs from gene families that have undergone lineage-specific duplications, including those with single duplications (one yeast gene to two human genes, 1:2) or higher-order expansions (1:>2) in the human lineage. We observe a variable pattern of replaceability across different ortholog classes, with an obvious trend towards differential replaceability inside gene families, rarely observing replaceability by all members of a family. We quantify the ability of various properties of the orthologs to predict replaceability, showing that in the case of 1:2 orthologs, replaceability is predicted largely by the divergence and tissue-specific expression of the human co-orthologs, i.e. the human proteins that are less diverged from their yeast counterpart and more ubiquitously expressed across human tissues more often replace their single yeast ortholog. These trends were consistent with in silico simulations demonstrating that when only one ortholog is replaceable, it tends to be the least diverged of the pair. Replaceability of yeast genes having more than two human co-orthologs was marked by retention of orthologous interactions in functional or protein networks as well as by more ancestral subcellular localization. Overall, we performed >400 human gene replaceability assays revealing 56 new human-yeast complementation pairs, thus opening up avenues to further functionally characterize these human genes in a simplified organismal context.
Aerosolized TLR Agonists Suppress Acute Sendai Virus Lung Infection and Chronic Airway Disease in Mice
Authors: Goldblatt David L. , Flores Jose R. , Valverde Ha Gabriella , Jaramillo Ana M. , Tkachman Sofya , Kirkpatrick Carson T. , Wali Shradha , Hernandez Belinda , Ost David E. , Scott Brenton L. , Chen Jichao , Evans Scott E. , Tuvim Michael J. , Dickey Burton F. 
Published: June 2019

AbstractRespiratory viral infections play central roles in the initiation, exacerbation and progression of asthma in humans. An acute paramyxoviral infection in mice can cause a chronic lung disease that resembles human asthma. We sought to determine whether reduction of Sendai virus lung burden in mice by stimulating innate immunity with aerosolized Toll-like receptor (TLR) agonists could attenuate the severity of chronic asthma-like lung disease. Treatment with 1 µM oligodeoxynucleotide (ODN) M362, an agonist of the TLR9 homodimer, and 4 µM Pam2CSK4 (Pam2), an agonist of the TLR2/6 heterodimer, within a few days before or after Sendai virus challenge, resulted in a ∼75% reduction in lung Sendai virus burden five days after challenge. The reduction in acute lung virus burden was associated with marked reductions 49 days after viral challenge in eosinophilic and lymphocytic lung inflammation, airway mucous metaplasia, lumenal mucus occlusion, and hyperresponsiveness to methacholine. Mechanistically, ODN/Pam2 treatment attenuated the chronic asthma phenotype by suppressing IL-33 production by type 2 pneumocytes, both by reducing the severity of acute infection and by downregulating Type 2 (allergic) inflammation. These data suggest that treatment of susceptible human hosts with aerosolized ODN and Pam2 at the time of a respiratory viral infection might attenuate the severity of the acute infection and reduce progression of asthma.One Sentence SummaryRespiratory viral infections can induce chronic airway disease, and we find that stimulating innate immunity within the lungs of mice reduces the severity of acute infection and development of a chronic asthma phenotype.
Reinforcement learning as an intermediate phenotype in psychosis? Deficits sensitive to illness stage but not associated with polygenic risk of schizophrenia in the general population
Authors: Montagnese M , Knolle F , Haarsma J , Griffin JD , Richards A , Vertes P , Kiddle B , Fletcher PC , Jones PB , Owen MJ , Fonagy P , Bullmore ET , Dolan R , Consortium NSPN , Moutoussis M , Goodyer I , Murray GK 
Published: June 2019

AbstractBackgroundSchizophrenia is a complex disorder in which the causal relations between risk genes and observed clinical symptoms are not well understood and the explanatory gap is too wide to be clarified without considering an intermediary level. Thus, we aimed to test the hypothesis of a pathway from molecular polygenic influence to clinical presentation occurring via deficits in reinforcement learning.MethodsWe administered a reinforcement learning task (Go/NoGo) that measures reinforcement learning and the effect of Pavlovian bias on decision making. We modelled the behavioural data with a hierarchical Bayesian approach (hBayesDM) to decompose task performance into its underlying learning mechanisms. Study 1 included controls (n= 29, F|M=0.81), At Risk Mental State for psychosis (ARMS, n= 23, F|M=0.35) and FEP (First-episode psychosis, n= 26, F|M=0.18). Study 2 included healthy adolescents (n= 735, F|M= 1.06), 390 of whom had their polygenic risk scores for schizophrenia (PRSs) calculated.ResultsPatients with FEP showed significant impairments in overriding Pavlovian conflict, a lower learning rate and a lower sensitivity to both reward and punishment. Less widespread deficits were observed in ARMS. PRSs did not significantly predict performance on the task in the general population, which only partially correlated with measures of psychopathology.ConclusionsReinforcement learning deficits are observed in first episode psychosis and, to some extent, in those at clinical risk for psychosis, and were not predicted by molecular genetic risk for schizophrenia in healthy individuals. The study does not support the role of reinforcement learning as an intermediate phenotype in psychosis.