bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiphospholipid antibody levels in early systemic lupus erythematosus: are they associated with subsequent mortality and vascular events?
Authors: Pericleous Charis , D’Souza Amrita , McDonnell Thomas , Ripoll Vera M , Leach Oliver , Isenberg David , Giles Ian , Rahman Anisur 
Published: May 2019

Abstract

Objectives
aPL are present in between 20 and 30% of patients with SLE. They can cause vascular events (VE) or pregnancy morbidity. aCL and anti-beta-2-glycoprotein I (anti-β2GPI) are measured in clinical practice. Domain I (DI) of β2GPI is the main site for aPL binding. We investigated the prevalence of IgG anti-DI, aCL and anti-β2GPI antibodies in early SLE and their association with mortality and development of VE.

Methods
Samples from 501 patients with SLE that had been obtained and stored early during their disease were tested for IgG anti-DI, aCL and anti-β2GPI antibodies by ELISA. LA status and history of VE were obtained by reviewing medical records. Kaplan–Meier analysis was used to investigate mortality and occurrence of VE, comparing groups with and without aPL in early disease.

Results
Of 501 patients, 190 (38%) had at least one of these aPL, of whom 112 had anti-DI alone. Of 276 patients with complete vascular history, 83 had experienced VE. The 39 patients who were double or triple-ELISA-positive for any combination of the three aPL were more likely to have or develop lupus anticoagulant (P&lt;0.0001) than those who were single-ELISA-positive or negative. In Kaplan–Meier analysis, they showed a trend towards developing more VE (P = 0.06).

Conclusion
IgG anti-DI antibodies were present in early serum samples from 29% of patients and were more common than IgG aCL or anti-β2GPI. There was some evidence suggesting that double or triple-ELISA-positivity for these antibodies identified a group with worse outcomes.
The ‘Dog Doctors’ of Edwardian London: Elite Canine Veterinary Care in the Early Twentieth Century
Authors: Skipper Alison 
Published: May 2019

Summary
This article offers the first historical account of Edwardian London’s elite canine veterinarians. Previous historiography identifies increasing veterinary interest in dogs as a mid-twentieth century phenomenon. Despite tension with the mainstream profession, however, an earlier group of specialist veterinarians provided sophisticated canine medical care to London society. Their activities included the policing and investigation of two key threats to the fashionable and lucrative ‘dog fancy’: the devastating infectious disease distemper and the issue of ‘faking’ (show ring cosmetic fraud). This prestigious work gave the canine veterinarians a competitive advantage over their various rivals and enabled the dog fancy to combat the unintended consequences of its own practices on the canine body. This article consequently reveals an early instance of veterinary specialisation, co-driven by client demands and professional politics, and foregrounds the importance of canine biology in the social history of pedigree dog breeding.
Phylogenomic Relationships of Diploids and the Origins of Allotetraploids in Dactylorhiza (Orchidaceae)
Authors: Brandrud Marie K , Baar Juliane , Lorenzo Maria T , Athanasiadis Alexander , Bateman Richard M , Chase Mark W , Hedrén Mikael , Paun Ovidiu 
Published: May 2019

Abstract
Disentangling phylogenetic relationships proves challenging for groups that have evolved recently, especially if there is ongoing reticulation. Although they are in most cases immediately isolated from diploid relatives, sets of sibling allopolyploids often hybridize with each other, thereby increasing the complexity of an already challenging situation. Dactylorhiza (Orchidaceae: Orchidinae) is a genus much affected by allopolyploid speciation and reticulate phylogenetic relationships. Here, we use genetic variation at tens of thousands of genomic positions to unravel the convoluted evolutionary history of Dactylorhiza. We first investigate circumscription and relationships of diploid species in the genus using coalescent and maximum likelihood methods, and then group 16 allotetraploids by maximum affiliation to their putative parental diploids, implementing a method based on genotype likelihoods. The direction of hybrid crosses is inferred for each allotetraploid using information from maternally inherited plastid RADseq loci. Starting from age estimates of parental taxa, the relative ages of these allotetraploid entities are inferred by quantifying their genetic similarity to the diploids and numbers of private alleles compared with sibling allotetraploids. Whereas northwestern Europe is dominated by young allotetraploids of postglacial origins, comparatively older allotetraploids are distributed further south, where climatic conditions remained relatively stable during the Pleistocene glaciations. Our bioinformatics approach should prove effective for the study of other naturally occurring, nonmodel, polyploid plant complexes.
Analysis of Spounaviruses as a Case Study for the Overdue Reclassification of Tailed Phages
Authors: Barylski Jakub , Enault François , Dutilh Bas E , Schuller Margo BP , Edwards Robert A , Gillis Annika , Klumpp Jochen , Knezevic Petar , Krupovic Mart , Kuhn Jens H , Lavigne Rob , Oksanen Hanna M , Sullivan Matthew B , Jang Ho Bin , Simmonds Peter , Aiewsakun Pakorn , Wittmann Johannes , Tolstoy Igor , Brister J Rodney , Kropinski Andrew M , Adriaenssens Evelien M 
Published: May 2019

Abstract
Tailed bacteriophages are the most abundant and diverse viruses in the world, with genome sizes ranging from 10 kbp to over 500 kbp. Yet, due to historical reasons, all this diversity is confined to a single virus order—Caudovirales, composed of just four families: Myoviridae, Siphoviridae, Podoviridae, and the newly created Ackermannviridae family. In recent years, this morphology-based classification scheme has started to crumble under the constant flood of phage sequences, revealing that tailed phages are even more genetically diverse than once thought. This prompted us, the Bacterial and Archaeal Viruses Subcommittee of the International Committee on Taxonomy of Viruses (ICTV), to consider overall reorganization of phage taxonomy. In this study, we used a wide range of complementary methods—including comparative genomics, core genome analysis, and marker gene phylogenetics—to show that the group of Bacillus phage SPO1-related viruses previously classified into the Spounavirinae subfamily, is clearly distinct from other members of the family Myoviridae and its diversity deserves the rank of an autonomous family. Thus, we removed this group from the Myoviridae family and created the family Herelleviridae—a new taxon of the same rank. In the process of the taxon evaluation, we explored the feasibility of different demarcation criteria and critically evaluated the usefulness of our methods for phage classification. The convergence of results, drawing a consistent and comprehensive picture of a new family with associated subfamilies, regardless of method, demonstrates that the tools applied here are particularly useful in phage taxonomy. We are convinced that creation of this novel family is a crucial milestone toward much-needed reclassification in the Caudovirales order.
AhR Activation in Pharmaceutical Development: Applying Liver Gene Expression Biomarker Thresholds to Identify Doses Associated With Tumorigenic Risks in Rats
Authors: Qin Chunhua , Aslamkhan Amy G , Pearson Kara , Tanis Keith Q , Podtelezhnikov Alexei , Frank Erika , Pacchione Stephen , Pippert Todd , Glaab Warren E , Sistare Frank D 
Published: May 2019

Abstract
Aryl hydrocarbon receptor (AhR) activation is associated with carcinogenicity of non-genotoxic AhR-activating carcinogens such as 2,3,7,8-tetrachlorodibenzodioxin (TCDD), and is often observed with drug candidate molecules in development and raises safety concerns. As downstream effectors of AhR signaling, the expression and activity of Cyp1a1 and Cyp1a2 genes are commonly monitored as evidence of AhR activation to inform carcinogenic risk of compounds in question. However, many marketed drugs and phytochemicals are reported to induce these Cyps modestly and are not associated with dioxin-like toxicity or carcinogenicity. We hypothesized that a threshold of AhR activation needs to be surpassed in a sustained manner in order for the dioxin-like toxicity to manifest, and a simple liver gene expression signature based on Cyp1a1 and Cyp1a2 from a short-term rat study could be used to assess AhR activation strength and differentiate tumorigenic dose levels from non-tumorigenic ones. To test this hypothesis, short-term studies were conducted in Wistar Han rats with 2 AhR-activating carcinogens (TCDD and PCB126) at minimally carcinogenic and noncarcinogenic dose levels, and 3 AhR-activating noncarcinogens (omeprazole, mexiletine, and canagliflozin) at the top doses used in their reported 2-year rat carcinogenicity studies. A threshold of AhR activation was identified in rat liver that separated a meaningful “tumorigenic-strength AhR signal” from a statistically significant AhR activation signal that was not associated with dioxin-like carcinogenicity. These studies also confirmed the importance of the sustainability of AhR activation for carcinogenic potential. A sustained activation of AhR above the threshold could thus be used in early pharmaceutical development to identify dose levels of drug candidates expected to exhibit dioxin-like carcinogenic potential.
Needlestack: an ultra-sensitive variant caller for multi-sample next generation sequencing data
Authors: Delhomme Tiffany M. , Avogbe Patrice H. , Gabriel Aurélie , Alcala Nicolas , Leblay Noemie , Voegele Catherine , Vallée Maxime , Chopard Priscilia , Chabrier Amélie , Abedi-Ardekani Behnoush , Gaborieau Valérie , Holcatova Ivana , Janout Vladimir , Foretová Lenka , Milosavljevic Sasa , Zaridze David , Mukeriya Anush , Brambilla Elisabeth , Brennan Paul , Scelo Ghislaine , Fernandez-Cuesta Lynnette , Byrnes Graham , Le Calvez-Kelm Florence , McKay James D. , Foll Matthieu 
Published: May 2019

ABSTRACTThe emergence of Next-Generation Sequencing (NGS) has revolutionized the way of reaching a genome sequence, with the promise of potentially providing a comprehensive characterization of DNA variations. Nevertheless, detecting somatic mutations is still a difficult problem, in particular when trying to identify low abundance mutations such as subclonal mutations, tumour-derived alterations in body fluids or somatic mutations from histological normal tissue. The main challenge is to precisely distinguish between sequencing artefacts and true mutations, particularly when the latter are so rare they reach similar abundance levels as artefacts. Here, we present needlestack, a highly sensitive variant caller, which directly learns from the data the level of systematic sequencing errors to accurately call mutations. Needlestack is based on the idea that the sequencing error rate can be dynamically estimated from analyzing multiple samples together. We show that the sequencing error rate varies across alterations, illustrating the need to precisely estimate it. We evaluate the performance of needlestack for various types of variations, and we show that needlestack is robust among positions and outperforms existing state-of-the-art method for low abundance mutations. Needlestack, along with its source code is freely available on the GitHub plateform: https://github.com/IARCbioinfo/needlestack.
A Novel Method for Calculating Mean Erythrocyte Age Using Erythrocyte Creatine
Authors: Kameyama Masashi , Koga Masafumi , Okumiya Toshika 
Published: May 2019

AbstractBackgroundsErythrocyte creatine (EC) decreases reflecting erythrocyte age.MethodsWe developed an EC model, which showed a bi- or mono-exponential relationship between mean erythrocyte age (MRBC) andEC. We reanalyzed the previously published data of 21 patients with hemolytic anemia which includedECand51Cr half-life.ResultsMRBCand logeECshowed excellent significant linearity (r= −0.9475,p <0.001), showing that it can be treated as a mono-exponential relationship within the studied range (EC: 1.45 – 11.76µmol/g Hb). We established an equation to obtainMRBC(days) fromEC(µmol/g Hb),MRBC= −22.84 logeEC+ 65.83.ConclusionThis equation allows calculation ofMRBCbased on EC which has practical applications such as the diagnosis of anemia.
Redundant and specific roles of cohesin STAG subunits in chromatin looping and transcription control
Authors: Casa Valentina , Gines Macarena Moronta , Gusmao Eduardo Gade , Slotman Johann A. , Zirkel Anne , Josipovic Natasa , Oole Edwin , van IJcken Wilfred F.J. , Houtsmuller Adriaan B. , Papantonis Argyris , Wendt Kerstin S. 
Published: May 2019

AbstractCohesin is a ring-shaped multiprotein complex that is crucial for 3D genome organization and transcriptional regulation during differentiation and development. It also confers sister chromatid cohesion and facilitates DNA damage repair. Besides its core subunits SMC3, SMC1A and RAD21, cohesin contains in somatic cells one of two orthologous STAG subunits, SA1 or SA2. How these variable subunits affect the function of the cohesin complex is still unclear. SA1- and SA2-cohesin were initially proposed to organize cohesion at telomeres and centromeres, respectively. Here, we uncover redundant and specific roles of SA1 and SA2 in gene regulation and chromatin looping using HCT116 cells with an auxin-inducible degron (AID) tag fused to either SA1 or SA2. Following rapid depletion of either subunit, we perform high resolution Hi-C, RNA-sequencing and sequential ChIP studies to show that SA1 and SA2 do not co-occupy individual binding sites and have distinct ways how they affect looping and gene expression. These findings are supported at the single cell level by single-molecule localizations via dSTORM super-resolution imaging. Since somatic and congenital mutations of the SA subunits are associated with cancer (SA2) and intellectual disability syndromes with congenital abnormalities (SA1 and SA2), we verified SA1-/SA2-dependencies using human neural stem cells, hence highlighting their importance for understanding particular disease contexts.
Acute inflammation alters energy metabolism in mice and humans: Role in sickness-induced hypoactivity, impaired cognition and delirium
Authors: Kealy John , Murray Carol , Griffin Eadaoin W. , Lopez-Rodriguez Ana Belen , Healy Dáire , Tortorelli Lucas Silva , Lowry John P. , Watne Leiv Otto , Cunningham Colm 
Published: May 2019

AbstractSystemic infection triggers a spectrum of metabolic and behavioral changes, collectively termed sickness behavior, that while adaptive for the organism, can affect mood and cognition. In vulnerable individuals, acute illness can also produce profound, maladaptive, cognitive dysfunction including delirium, but our understanding of delirium pathophysiology remains limited. Here we used bacterial lipopolysaccharide (LPS) in C57BL/6J mice and acute hip fracture in humans to address whether disrupted energy metabolism contributes to inflammation-induced behavioral and cognitive changes. LPS (250 μg/kg) induced hypoglycemia, which was mimicked by IL-1β (25 μg/kg) but not prevented in IL-1RI-/-mice, nor by IL-1RA (10 mg/kg). LPS suppression of locomotor activity correlated with blood glucose concentration, was mitigated by exogenous glucose (2 g/kg) and was exacerbated by 2-deoxyglucose glycolytic inhibition, which prevented IL-1β synthesis. Using the ME7 model of chronic neurodegeneration, to examine vulnerability of the diseased brain to acute stressors, we showed that LPS (100 μg/kg) produced acute cognitive dysfunction, selectively in those animals. These acute cognitive impairments were mimicked by insulin (11.5 IU/kg) and mitigated by glucose, demonstrating that acutely reduced glucose metabolism impairs cognition in the vulnerable brain. To test whether these acute changes might predict altered carbohydrate metabolism during delirium, we assessed glycolytic metabolite levels in cerebrospinal fluid (CSF) in humans during delirium, triggered by acute inflammatory trauma. Hip fracture patients showed elevated CSF lactate and pyruvate during delirium, consistent with altered brain energy metabolism. Collectively the data suggest that disruption of energy metabolism drives behavioral and cognitive consequences of acute systemic inflammation.
Single-cell RNA-seq analysis reveals the crucial role of Collagen Triplex Helix Repeat Containing 1 (CTHRC1) cardiac fibroblasts for ventricular remodeling after myocardial infarction
Authors: Ruiz-Villalba Adrian , Romero Juan P. , Hernandez Silvia C. , Vilas-Zornoza Amaia , Fortelny Nikolaus , Castro Laura , Martin-Uriz Patxi San , Lorenzo-Vivas Erika , García-Olloqui Paula , Palacios Marcel , Gavira Juan José , Bastarrika Gorka , Janssens Stefan , Iglesias Elena , Abizanda Gloria , de Morentin Xabier Martinez , Bock Christoph , Alignani Diego , Medal Gema , Gomez-Cabrero David , Prudovsky Igor , Jin Yong-Ri , Ryzhov Sergey , Yin Haifeng , Pelacho Beatriz , Lindner Volkhard , Lara-Astiaso David , Prósper Felipe 
Published: May 2019

ABSTRACTCardiac fibroblasts have a central role during the ventricular remodeling process associated with different types of cardiac injury. Recent studies have shown that fibroblasts do not respond homogeneously to heart damage, suggesting that the adult myocardium may contain specialized fibroblast subgroups with specific functions. Due to the limited set ofbona fidefibroblast markers, a proper characterization of fibroblast population dynamics in response to cardiac damage is still missing. Using single-cell RNA-seq, we identified and characterized a fibroblast subpopulation that emerges in response to myocardial infarction (MI) in a murine model. These activated fibroblasts exhibit a clear pro-fibrotic signature, express high levels of the hormone CTHRC1 and of the immunomodulatory co-receptor CD200 and localize to the injured myocardium. Combining epigenomic profiling with functional assays, we showSox9and the non-canonical TGF-β signaling as important regulators mediating their response to cardiac damage. We show that the absence of CTHRC1, in this activated fibroblast subpopulation, results in pronounced lethality due to ventricular rupture in a mouse model of myocardial infarction. Finally, we find evidence for the existence of similar mechanisms in a pig pre-clinical model of MI and establish a correlation betweenCTHRC1levels and cardiac function after MI.
Gli3 regulates vomeronasal neurogenesis, olfactory ensheathing cell formation and GnRH-1 neuronal migration
Authors: Taroc Ed Zandro M. , Naik Ankana , Lin Jennifer M. , Peterson Nicolas B. , Keefe David L. , Genis Elizabet , Fuchs Gabriele , Balasubramanian Ravikumar , Forni Paolo E. 
Published: May 2019

AbstractDuring mammalian development, gonadotropin-releasing-hormone-1 neurons (GnRH-1ns) migrate from the developing vomeronasal organ (VNO) into the brain asserting control of pubertal onset and fertility. Recent data suggest that correct development of the olfactory ensheathing cells (OEC) is imperative for normal GnRH-1 neuronal migration. However, the full ensemble of molecular pathways that regulate OEC development remains to be fully deciphered. Loss-of-function of the transcription factor Gli3 is known to disrupt olfactory development, however, if Gli3 plays a role in GnRH-1 neuronal development is unclear. By analyzing Gli3 extra-toe mutants (Gli3Xt/Xt), we found that Gli3 loss-of-function compromises the onset of achaete-scute family bHLH transcription factor 1 (Ascl-1) positive vomeronasal progenitors and the formation of OEC in the nasal mucosa. Surprisingly, GnRH-1 neurogenesis was intact in Gli3Xt/Xtmice but they displayed significant defects in GnRH-1 neuronal migration. In contrast, Ascl-1nullmutants showed reduced neurogenesis for both vomeronasal and GnRH-1ns but less severe defects in OEC development. These observations suggest that Gli3 is critical for OEC development in the nasal mucosa and subsequent GnRH-1 neuronal migration. However, the non-overlapping phenotypes between Ascl-1 and Gli3 mutants indicate that Ascl-1, while crucial for GnRH-1 neurogenesis, is not required for normal OEC development. Since Kallmann syndrome (KS) is characterized by abnormal GnRH migration, we examined whole exome sequencing data from KS subjects. We identified and validated aGLI3loss-of-function variant in a KS individual. These findings provide new insights into GnRH-1 and OECs development and demonstrate that humanGLI3mutations contribute to KS etiology.Significance statementThe transcription factor Gli3 is necessary for correct development of the olfactory system. However, if Gli3 plays a role in controlling GnRH-1 neuronal development has not been addressed. We found that Gli3 loss-of-function compromises the onset of Ascl1+ vomeronasal progenitors, formation of olfactory ensheathing cells in the nasal mucosa and impairs GnRH-1 neuronal migration to the brain. By analyzing Ascl1 null mutants we dissociated the neurogenic defects observed in Gli3 mutants from lack of olfactory ensheathing cells in the nasal mucosa, moreover, we discovered that Ascl1 is necessary for GnRH-1 ontogeny. Analyzing human whole exome sequencing data, we identified aGLI3loss-of-function variant in a KS individual. Our data suggest thatGLI3is a candidate gene contributing to KS etiology.
Multiplexed measurement of protein biomarkers in high-frequency longitudinal dried blood spot (DBS) samples: characterization of inflammatory responses
Authors: Anderson N. Leigh , Razavi Morteza , Pope Matthew E. , Yip Richard , Pearson Terry W. 
Published: May 2019

AbstractA detailed understanding of changes in blood protein biomarkers occuring in individuals over time would enable truly personalized approaches to health and disease monitoring. Such measurements could reveal smaller, earlier departures from normal baseline levels of biomarkers thus allowing better disease detection and treatment monitoring. Current practice, however, generally involves infrequent, sporadic biomarker testing, and this undersampling likely fails to capture important biological phenomena. Here we report the use of a robust multiplex immuno-mass spectrometric method (SISCAPA) to measure a panel of clinically-relevant proteins in a unique collection of 1,522 dried blood spots collected longitudinally by 8 individuals over periods of up to 9 years, with daily sampling during some intervals. Analytical workflow CVs of 2-6% for most assays were achieved by normalizing DBS plasma volume using a set of 3 minimally varying proteins, facilitating temporal analysis of both high- and low-amplitude biomarker changes compared to personalized baselines. The biomarkers included a panel of 9 positive and 5 negative acute phase response (inflammatory) proteins, allowing longitudinal analysis of inflammation markers associated with major and minor infections, influenza vaccination, recovery from hip-replacement surgery and Crohn’s disease. The results illustrate complex time-dependent “biomarker trajectories” on multiple timescales and provide a basis for detailed personalized models of inflammation dynamics. The striking stability of most biomarker protein levels over time, combined with the convenience of self-sampling and low cost of multiplexed measurements using mass spectrometry, provide a new window into the temporal dynamics of disease processes. The extensive results obtained using this high throughput approach offer a new source of precision biomarker ‘big data’ amenable to machine learning approaches and application to more personalized health monitoring.