bluuebunny/crossref_metadata_2025_split huggingface dataset:
Professionals and populists: the making of a free market for medicine in the United States, 1787–1860
Authors: Habinek Jacob , Haveman Heather A 
Published: December 2018

AbstractIn the early decades of the 19th century, physicians in the USA enjoyed unquestioned authority in medicine and increasing state recognition. But by mid-century, their monopoly had given way to a raucous free market for medical care. To explain the causes and consequences of this dismantling of a professional monopoly, we draw on political sociology. We argue that to maintain a monopoly, a dominant profession must defend its cultural authority against rival claims and preserve its institutional support from the state. A dominant profession can lose its monopoly if rival occupations mobilize to challenge its cultural authority and if populist political coalitions mobilize to repeal laws upholding professional monopolies. Our analysis, which covers all states in the Union by 1860, reveals that the dynamics of contention, both within the system of professions and in the wider political arena, can erode the foundations of professional monopolies.
Effect of maternal diet on select fecal bacteria of foals
Authors: Pyles Morgan B , Fowler Ashley L , Bill Veronica T , Harlow Brittany E , Crum Andrea D , Hayes Susan H , Flythe Michael D , Lawrence Laurie M 
Published: December 2018

Abstract
Adult horses depend on the microbial community in the hindgut to digest fiber and produce short-chain fatty acids that are use for energy. Colonization of the foal gastrointestinal tract is essential to develop this symbiosis. However, factors affecting colonization are not well understood. The objectives of this study were to evaluate the age-related changes and effects of maternal diet on select fecal bacterial groups in foals from 1 to 28 d of age. Thoroughbred foals (n = 18) were from dams fed forage and one of two concentrates: an oat-based (OB) or corn and wheat middlings-based (CWB) pelleted concentrate. The mares had access to assigned concentrates, along with a mixed hay and cool-season grass pasture, 28 d before and 28 d after parturition. Fecal samples were collected from foals at 1 d (14 to 36 h), 4, 14, and 28 d after birth. Fecal samples were serially diluted with phosphate-buffered saline before inoculation of enriched, selective media to enumerate Lactobacillus spp., amylolytic bacteria, and cellulolytic bacteria. Enumeration data were log-transformed then analyzed with mixed model analysis of variance with repeated measures (SAS 9.3) to test the main effects of maternal diet (OB or CWB), time of sample, and interaction between maternal diet and time. Cellulolytic bacteria first appeared in foal feces between 4 and 14 d of age and increased with age (P &lt; 0.05). Amylolytic bacteria and lactobacilli were abundant at 1 d and then increased with age (P &lt; 0.05). There was an interaction between maternal diet and time for Lactobacillus spp. with OB foals having more lactobacilli than CWB foals at 1 and 4 d (P &lt; 0.05); however, there were no differences observed at 14 d (P &gt; 0.05). Maternal diet did not influence amylolytic or cellulolytic bacteria (P &gt; 0.05). These results indicate that colonization of the hindgut is a sequential process beginning early in the foal’s life and that maternal diet may influence some bacteria in the gastrointestinal tract of foals.
Genetics of fasting indices of glucose homeostasis using GWIS unravels tight relationships with inflammatory markers
Authors: Fedko Iryna O. , Nivard Michel G. , Hottenga Jouke-Jan , Zudina Liudmila ,   Cross Consortia Pleiotropy (XC-Pleiotropy) Group, CHARGE Inflammation working group, Balkhiyarova Zhanna , Chasman Daniel I. , Ganesh Santhi , Huang Jie , Nalls Mike A. , O’Donnell Christopher J. , Paré Guillaume , Ridker Paul M. ,   Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) Investigators, Mägi Reedik , Kaakinen Marika , Prokopenko Inga , Boomsma Dorret I. 
Published: December 2018

AbstractPurposeHomeostasis Model Assessment of β-cell function and Insulin Resistance (HOMA-B/-IR) indices are informative about the pathophysiological processes underlying type 2 diabetes (T2D). Data on both fasting glucose and insulin levels are required to calculate HOMA-B/-IR, leading to underpowered Genome-Wide Association studies (GWAS) of these traits.MethodsWe overcame such power loss issues by implementing Genome-Wide Inferred Statistics (GWIS) approach and subsequent dense genome-wide imputation of HOMA-B/-IR summary statistics with SS-imp to 1000 Genomes project variant density, reaching an analytical sample size of 75,240 European individuals without diabetes. We dissected mechanistic heterogeneity of glycaemic trait/T2D loci effects on HOMA-B/-IR and their relationships with 36 inflammatory and cardiometabolic phenotypes.ResultsWe identified one/three novel HOMA-B (FOXA2)/HOMA-IR (LYPLAL1, PER4,PPP1R3B) loci. We detected novel strong genetic correlations between HOMA-IR/-B and Plasminogen Activator Inhibitor 1 (PAI-1, rg=0.92/0.78, P=2.13×10-4/2.54×10-3). HOMA-IR/-B were also correlated with C-Reactive Protein (rg=0.33/0.28, P=4.67×10-3/3.65×10-3). HOMA-IR was additionally correlated with T2D (rg=0.56, P=2.31×10-9), glycated haemoglobin (rg=0.28, P=0.024) and adiponectin (rg=-0.30, P=0.012).ConclusionUsing innovative GWIS approach for composite phenotypes we report novel evidence for genetic relationships between fasting indices of insulin resistance/beta-cell function and inflammatory markers, providing further support for the role of inflammation in T2D pathogenesis.
Namdinator - Automatic Molecular Dynamics flexible fitting of structural models into cryo-EM and crystallography experimental maps
Authors: Kidmose Rune Thomas , Juhl Jonathan , Nissen Poul , Boesen Thomas , Karlsen Jesper Lykkegaard , Pedersen Bjørn Panyella 
Published: December 2018

AbstractModel building into experimental maps is a key element of structural biology, but can be both time consuming and error-prone. Here we present Namdinator, an easy-to-use tool that enables the user to run a Molecular Dynamics Flexible Fitting (MDFF) simulation in an automated manner through a pipeline system. Namdinator will modify an atomic model to fit within cryo-EM or crystallography density maps, and can be used advantageously for both the initial fitting of models, and for a geometrical optimization step to correct outliers, clashes and other model problems. We have benchmarked Namdinator against 39 deposited models and maps from cryo-EM and observe model improvements in 34 of these cases (87%). Clashes between atoms were reduced, and model-to-map fit and overall model geometry were improved, in several cases substantially. We show that Namdinator is able to model large scale conformational changes compared to the starting model. Namdinator is a fast and easy way to create suitable initial models for both cryo-EM and crystallography. It can fix model errors in the final steps of model building, and is usable for structural model builders at all skill levels. Namdinator is available as a web service (https://namdinator.au.dk), or can be run locally as a command-line tool.SynopsisA pipeline tool called Namdinator is presented that enables the user to run a Molecular Dynamics Flexible Fitting (MDFF) simulation in a fully automated manner, both online and locally. This provides a fast and easy way to create suitable initial models for both cryo-EM and crystallography and help fix errors in the final steps of model building.
Sex-dependent dominance maintains migration supergene in rainbow trout
Authors: Pearse Devon E. , Barson Nicola J. , Nome Torfinn , Gao Guangtu , Campbell Matthew A. , Abadía-Cardoso Alicia , Anderson Eric C. , Rundio David E. , Williams Thomas H. , Naish Kerry A. , Moen Thomas , Liu Sixin , Kent Matthew , Minkley David R. , Rondeau Eric B. , Brieuc Marine S. O. , Rød Sandve Simen , Miller Michael R. , Cedillo Lucydalila , Baruch Kobi , Hernandez Alvaro G. , Ben-Zvi Gil , Shem-Tov Doron , Barad Omer , Kuzishchin Kirill , Garza John Carlos , Lindley Steven T. , Koop Ben F. , Thorgaard Gary H. , Palti Yniv , Lien Sigbjørn 
Published: December 2018

AbstractTraits with different fitness optima in males and females cause sexual conflict when they have a shared genetic basis. Heteromorphic sex chromosomes can resolve this conflict and protect sexually antagonistic polymorphisms but accumulate deleterious mutations. However, many taxa lack differentiated sex chromosomes, and how sexual conflict is resolved in these species is largely unknown. Here we present a chromosome-anchored genome assembly for rainbow trout (Oncorhynchus mykiss) and characterize a 56 Mb double-inversion supergene that mediates sex-specific migration through sex-dependent dominance, a mechanism that reduces sexual conflict. The double-inversion contains key photosensory, circadian rhythm, adiposity, and sexual differentiation genes and displays frequency clines associated with latitude and temperature, revealing environmental dependence. Our results constitute the first example of sex-dependent dominance across a large autosomal supergene, a novel mechanism for sexual conflict resolution capable of protecting polygenic sexually antagonistic variation while avoiding the homozygous lethality and deleterious mutation load of heteromorphic sex chromosomes.
Simultaneous profiling of chromatin accessibility and methylation on human cell lines with nanopore sequencing
Authors: Lee Isac , Razaghi Roham , Gilpatrick Timothy , Molnar Michael , Sadowski Norah , Simpson Jared T. , Sedlazeck Fritz J. , Timp Winston 
Published: December 2018

ABSTRACTUnderstanding how the genome and the epigenome work together to control gene transcription has applications in our understanding of diseases such as human cancer. In this study, we combine the ability of NOMe-seq to simultaneously evaluate CpG methylation and chromatin accessibility, with long-read nanopore sequencing technology, a method we call nanoNOMe. We generated >60Gb whole-genome nanopore sequencing data for each of four human cell lines (GM12878, MCF-10A, MCF-7, MDA-MB-231) including repetitive regions inaccessible by short read sequencing. Using the long reads, we find that we can observe phased methylation and chromatin accessibility, large scale pattern changes, and genetic changes such as structural variations from a single assay.
Calcium-Induced Differentiation in Normal Human Colonoid Cultures
Authors: Attili Durga , McClintock Shannon D. , Rizvi Areeba H. , Pandya Shailja , Rehman Humza , Nadeem Daniyal M , Richter Aliah , Thomas Dafydd , Dame Michael K. , Turgeon D. Kim , Varani James , Aslam Muhammad Nadeem 
Published: December 2018

ABSTRACTColonoid cultures were established from histologically-normal human colon tissue and maintained in a low-calcium (0.25 mM) medium or in medium supplemented with an amount of calcium (1.5 - 3.0 mM) that was shown in a previous study to induce differentiation in colonoids derived from large adenomas. Calcium alone was compared to Aquamin, a multi-mineral natural product that contains magnesium and detectable levels of 72 additional trace elements in addition to calcium. Unlike the previously-studied tumor-derived colonoids (which remained un-differentiated in the absence of calcium-supplementation), normal tissue colonoids underwent differentiation as indicated by gross and microscopic appearance, a low proliferative index and high-level expression of cytokeratin 20 (CK20) in the absence of intervention. Only modest additional changes were seen in these parameters with either calcium alone or Aquamin (providing up to 3.0 mM calcium). In spite of this, proteomic analysis and immunohistochemistry revealed that both interventions induced strong up-regulation of proteins that promote cell-cell and cell-matrix adhesive functions, barrier formation and tissue integrity. Transmission electron microscopy revealed an increase in desmosomes in response to intervention. These findings demonstrate that histologically normal human colonoids can undergo differentiation in the presence of a low ambient calcium concentration. However, higher calcium levels can induce elaboration of proteins that promote cell-cell and cell-matrix adhesion. These changes could lead to improved barrier function and improved colon tissue health.
DeepCell Kiosk: Scaling deep learning-enabled cellular image analysis with Kubernetes
Authors: Bannon Dylan , Moen Erick , Schwartz Morgan , Borba Enrico , Kudo Takamasa , Greenwald Noah , Vijayakumar Vibha , Chang Brian , Pao Edward , Osterman Erik , Graf William , Van Valen David 
Published: December 2018

AbstractDeep learning is transforming the analysis of biological images but applying these models to large datasets remains challenging. Here we describe the DeepCell Kiosk, cloud-native software that dynamically scales deep learning workflows to accommodate large imaging datasets. To demonstrate the scalability and affordability of this software, we identified cell nuclei in 106 1-megapixel images in ~5.5 h for ~$250, with a sub-$100 cost achievable depending on cluster configuration. The DeepCell Kiosk can be downloaded at https://github.com/vanvalenlab/kiosk-console; a persistent deployment is available at https://deepcell.org.
Experimental colitis drives enteric alpha-synuclein accumulation and Parkinson-like brain pathology
Authors: Grathwohl Stefan , Quansah Emmanuel , Maroof Nazia , Steiner Jennifer A. , Spycher Liz , Benmansour Fethallah , Duran-Pacheco Gonzalo , Siebourg-Polster Juliane , Oroszlan-Szovik Krisztina , Remy Helga , Haenggi Markus , Stawiski Marc , Sehlhausen Matthias , Maliver Pierre , Wolfert Andreas , Emrich Thomas , Madaj Zachary , Galvis Martha L. Escobar , Mueller Christoph , Herrmann Annika , Brundin Patrik , Britschgi Markus 
Published: December 2018

AbstractIntraneuronal accumulation of α-synuclein (αSyn) is key in the pathogenesis of Parkinson’s disease (PD). Published studies suggest that this process begins in the enteric nervous system (ENS) and propagates into the brain decades before clinical diagnosis of PD. The triggers and mechanisms underlying the accumulation of αSyn remain unknown but evidence is growing, that immune pathways and in particular colitis may play a critical role. Here we demonstrate that patients with inflammatory bowel disease (IBD) exhibit αSyn accumulation in their colon. We then confirmed in an experimental model of IBD that intestinal inflammation can trigger αSyn accumulation in the ENS of wildtype and αSyn transgenic mice. We discovered that the type and degree of inflammation modulates the extent of αSyn accumulation in the colon and that macrophage-related signaling limits this process. Remarkably, experimental colitis at three months of age exacerbated the accumulation of aggregated phospho-Serine 129 αSyn in the midbrain, including the substantia nigra, in 21-month but not 9-month-old αSyn transgenic mice. This was accompanied by loss of nigral tyrosine hydroxylase-immunoreactive neurons, another neuropathological hallmark of PD. Together, our data suggest a critical role for intestinal inflammation in the initiation and progression of PD.
Motor skill learning decreases motor variability and increases planning horizon
Authors: Bashford Luke , Kobak Dmitry , Diedrichsen Jörn , Mehring Carsten 
Published: December 2018

AbstractWe investigated motor skill learning using a path tracking task, where human subjects had to track various curved paths at a constant speed while maintaining the cursor within the path width. Subjects’ accuracy increased with practice, even when tracking novel untrained paths. Using a “searchlight” paradigm, where only a short segment of the path ahead of the cursor was shown, we found that subjects with a higher tracking skill differed from the novice subjects in two respects. First, they had lower motor variability, in agreement with previous findings. Second, they took a longer section of the future path into account when performing the task, i.e. had a longer planning horizon. We estimate that between one third and one half of the performance increase was due to the increase in planning horizon. An optimal control model with a fixed horizon (receding horizon control) that increases with tracking skill quantitatively captured the subjects’ movement behaviour. These findings demonstrate that human subjects not only increase their motor acuity but also their planning horizon when acquiring a motor skill.New and NoteworthyWe show that when learning a motor skill humans are using information about the environment from an increasingly longer amount of the movement path ahead to improve performance. Crucial features of the behavioural performance can be captured by modelling the behavioural data with a receding horizon optimal control model.
Stimulus Salience Determines the Defensive Behaviors Elicited by Aversively Conditioned Compound Auditory Stimuli
Authors: Hersman Sarah , Anthony Todd E. 
Published: December 2018

SUMMARYAnimals exhibit distinct patterns of defensive behavior according to their perceived imminence of potential threats. Ethoexperimental [1, 2] and aversive conditioning [3-5] studies indicate that as the probability of directly encountering a threat increases, animals shift from behaviors aimed at avoiding detection (e.g. freezing) to escape (e.g. undirected flight). What are the neural mechanisms responsible for assessing threat imminence and controlling appropriate behavioral responses? Fundamental to addressing these questions has been the development of behavioral paradigms in mice in which well-defined threat-associated sensory stimuli reliably and robustly elicit passive or active defensive responses [6, 7]. In serial compound stimulus (SCS) fear conditioning, repeated pairing of sequentially presented tone (CS1) and white noise (CS2) auditory stimuli with footshock (US) yields learned freezing and flight responses to CS1 and CS2, respectively [6]. Although this white noise-induced transition from freezing to flight would appear to reflect increased perceived imminence due to the US being more temporally proximal to CS2 than CS1, this model has not been directly tested. Surprisingly, we find that audio frequency properties and sound pressure levels, not temporal relationship to the US, determine the defensive behaviors elicited by SCS conditioned auditory stimuli. Notably, auditory threat stimuli that most potently elicit high imminence behaviors include frequencies to which mouse hearing is most sensitive. These results argue that, as with visual threats [8], perceived imminence and resulting intensity of defensive responses scale with the salience of auditory threat stimuli.
The impact of natural selection on the evolution and function of placentally expressed galectins
Authors: Ely Zackery A. , Moon Jiyun M. , Sliwoski Gregory R. , Sangha Amandeep K. , Shen Xing-Xing , Labella Abigail L. , Meiler Jens , Capra John A. , Rokas Antonis 
Published: December 2018

AbstractImmunity genes have repeatedly experienced natural selection during mammalian evolution. Galectins are carbohydrate-binding proteins that regulate diverse immune responses, including maternal-fetal immune tolerance in placental pregnancy. Seven human galectins, four conserved across vertebrates and three specific to primates, are involved in placental development. To comprehensively study the molecular evolution of these galectins both across mammals and within humans, we conducted a series of between-and within-species evolutionary analyses. By examining patterns of sequence evolution between species, we found that primate-specific galectins showed uniformly high substitution rates, whereas two of the four other galectins experienced accelerated evolution in primates. By examining human population genomic variation, we found that galectin genes and variants, including variants previously linked to immune diseases, showed signatures of recent positive selection in specific human populations. By examining one nonsynonymous variant in Galectin-8 previously associated with autoimmune diseases, we further discovered that it is tightly linked to three other nonsynonymous variants; surprisingly, the global frequency of this four-variant haplotype is ∼50%. To begin understanding the impact of this major haplotype on Galectin-8 protein structure, we modeled its 3D protein structure and found that it differed substantially from the reference protein structure. These results suggest that placentally expressed galectins experienced both ancient and more recent selection in a lineage-and population-specific manner. Furthermore, our discovery that the major Galectin-8 haplotype is structurally distinct from and more commonly found than the reference haplotype illustrates the significance of understanding the evolutionary processes that sculpted variants associated with human genetic disease.
HSF2 protects against proteotoxicity by maintaining cell-cell adhesion
Authors: Joutsen Jenny , Da Silva Alejandro J. , Budzynski Marek A. , Luoto Jens C. , de Thonel Aurelie , Concordet Jean-Paul , Mezger Valérie , Sabéran-Djoneidi Délara , Henriksson Eva , Sistonen Lea 
Published: December 2018

ABSTRACTCellular ability to maintain proper protein homeostasis (proteostasis) is essential for survival upon protein-damaging conditions. Heat shock transcription factor 2 (HSF2) is one of the human HSFs activated in response to proteotoxic stress. HSF2 is dispensable for cell survival during acute heat stress, but its amount and DNA-binding activity increase under prolonged proteotoxic stress conditions, such as proteasome inhibition. Nevertheless, the specific role(s) of HSF2 and the global HSF2-dependent gene expression profile during sustained stress have remained elusive. We found that HSF2 is required for cell survival during prolonged proteotoxicity, as shown by treating wild-type and HSF2-deficient human osteosarcoma U2OS cells with the proteasome inhibitor Bortezomib. Strikingly, our RNA-seq analyses revealed that HSF2 disruption leads to marked downregulation of cadherin superfamily genes and subsequent functional impairment of cadherin-mediated cell-cell adhesion. We propose HSF2 as a key regulator of genes belonging to the cadherin superfamily. We also demonstrate that HSF2-dependent downregulation of cadherin-mediated cell-cell adhesion predisposes U2OS cells to Bortezomib-induced proteotoxic stress. In conclusion, we show that by maintaining cell-cell adhesion HSF2 is essential for cell survival and thereby we describe a novel regime in the HSF-mediated protection against stress-induced protein damage.