bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blood-brain barrier dysfunction in aging induces hyper-activation of TGF-beta signaling and chronic yet reversible neural dysfunction
Authors: Senatorov V.V. , Friedman A.R. , Milikovsky D.Z. , Ofer J. , Saar-Ashkenazy R. , Charbash A. , Jahan N. , Chin G. , Mihaly E. , Lin J.M. , Ramsay H.J. , Moghbel A. , Preininger M.K. , Eddings C.R. , Harrison H.V. , Patel R. , Shen Y. , Ghanim H. , Sheng H. , Veksler R. , Sudmant P.H. , Becker A. , Hart B. , Rogawski M.A. , Dillin A. , Friedman A. , Kaufer D. 
Published: February 2019

AbstractAging involves a decline in neural function that contributes to cognitive impairment and disease. However, the mechanisms underlying the transition from a young-and-healthy to aged-and-dysfunctional brain are not well understood. Here, we report breakdown of the vascular blood-brain barrier (BBB) in aging humans and rodents, which begins as early as middle age and progresses to the end of the lifespan. Gain-of-function and loss-of-function manipulations show that this BBB dysfunction triggers hyperactivation of transforming growth factor β (TGFβ) signaling in astrocytes, which is necessary and sufficient to cause neural dysfunction and age-related pathology. Specifically, infusion of the serum protein albumin into the young brain (mimicking BBB leakiness) induced astrocytic TGFβ signaling and an aged brain phenotype including aberrant electrocorticographic activity, vulnerability to seizures, and cognitive impairment. Furthermore, conditional genetic knockdown of astrocytic TGFβ receptors, or pharmacological inhibition of TGFβ signaling, reversed these symptomatic outcomes in aged mice. Finally, we found that this same signaling pathway is activated in aging human subjects with BBB dysfunction. Our study identifies dysfunction in the neurovascular unit as one of the earliest triggers of neurological aging, and demonstrates that the aging brain may retain considerable latent capacity which can be revitalized by therapeutic inhibition of TGFβ signaling.
The broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents acute microgliosis and cognitive decline in a mouse model of perioperative neurocognitive disorders
Authors: Miller-Rhodes Patrick , Kong Cuicui , Baht Gurpreet S. , Rodriguiz Ramona M. , Wetsel William C. , Gelbard Harris A. , Terrando Niccolò 
Published: February 2019

AbstractPerioperative neurocognitive disorders (PND), including delirium and postoperative cognitive dysfunction, are serious complications that afflict up to 50% of surgical patients and for which there are no disease-modifying therapeutic options. Here, we test whether prophylactic treatment with the broad spectrum mixed-lineage kinase 3 inhibitor URMC-099 prevents surgery-induced neuroinflammation and cognitive impairment in a translational model of orthopedic surgery-induced PND. We used a combination of two-photon scanning laser microscopy and CLARITY with light-sheet microscopy to define surgery-induced changes in microglial dynamics and morphology. Orthopedic surgery induced widespread microglial activation in the hippocampus and cortex that accompanied impairments in episodic memory. URMC-099 prophylaxis prevented these neuropathological sequelae without impacting bone fracture healing. Together, these findings provide compelling evidence for the advancement of URMC-099 as a therapeutic option for PND.
Resilient Living Materials Built By Printing Bacterial Spores
Authors: González Lina M. , Voigt Christopher A. 
Published: February 2019

AbstractA route to advanced multifunctional materials is to embed them with living cells that can perform sensing, chemical production, energy scavenging, and actuation. A challenge in realizing this potential is that the conditions for keeping cells alive are not conducive to materials processing and require a continuous source of water and nutrients. Here, we present a 3D printer that can mix material and cell streams in a novel printhead and build 3D objects (up to 2.5 cm by 1 cm by 1 cm). Hydrogels are printed using 5% agarose, which has a low melting temperature (65°C) consistent with thermophilic cells, a rigid storage modulus (G’= 6.5 × 104), exhibits shear thinning, and can be rapidly hardened upon cooling to preserve structural features. Spores ofB. subtilisare printed within the material and germinate on its exterior, including spontaneously in cracks and new surfaces exposed by tears. By introducing genetically engineered bacteria, the materials can sense chemicals (IPTG, xylose, or vanillic acid). Further, we show that the spores are resilient to extreme environmental stresses, including desiccation, solvents (ethanol), high osmolarity (1.5 mM NaCl), 365 nm UV light, and γ-radiation (2.6 kGy). The construction of 3D printed materials containing spores enables the living functions to be used for applications that require long-term storage, in-field functionality, or exposure to uncertain environmental stresses.
Obesity alters mobility and adult neurogenesis, but not hippocampal dependent learning in ob/ob mice
Authors: Bracke Alexander , Domanska Grazyna , Bracke Katharina , Harzsch Steffen , van den Brandt Jens , Bröker Barbara , von Bohlen und Halbach Oliver 
Published: February 2019

AbstractsBackgroundObesity has become a severe problem among the world’s population with clearly increasing prevalence over the last decades. Because obesity is associated with several comorbidities (e.g. hypertension or cancer) it constitutes an increasing burden for the health care system. Correlations between obesity and cognition have been studied in humans with ambivalent results. Here, we studied the effects of obesity on hippocampus dependent learning and memory and cell morphology in a mouse model of obesity.MethodsThe body mass of male and female Lep+/+(wt) and Lepob/ob(ob/ob) animals with access to food and water ad libitum was measured between postnatal day 60-200 and animals with clear adiposity (4-6 months) were further analyzed. Adult hippocampal neurogenesis in the dentate gyrus was examined using phosphohistone H3 as a marker for proliferation, doublecortin as a marker for differentiation and caspase3 as a marker for apoptosis. Moreover, the density of dendritic spines on apical and basal dendrites of pyramidal neurons of the cornu ammonis 1 (CA1) were analyzed using Golgi impregnation. In addition, mice were subjected to the open field and Morris water maze test in order to analyze locomotor activity and spatial learning.ResultsThe body weight of ob/ob mice nearly doubled during the first 120 postnatal days. Adult hippocampal neurogenesis was reduced in ob/ob mice due to reduced cell proliferation. Dendritic spine densities in the hippocampal area CA1 were not altered in ob/ob mice. Four to six months old ob/ob mice showed reduced locomotor activity in the open field test but similar performance in the Morris water maze compared to control mice.ConclusionOur data show that alterations in adult neurogenesis in leptin-deficient mice are not associated with an impairment in spatial learning abilities. Moreover, ob/ob mice are inconspicuous in the Morris water maze and do not display altered spine densities in the hippocampus, suggesting that obesity does not have a severe impact upon hippocampal neuronal plasticity and spatial learning.
A pivotal role for Nrf2 in endothelial detachment- implications for endothelial erosion of stenotic plaques
Authors: Satta Sandro , McElroy Michael , Langford Smith Alex , Ferris Glenn R , Teasdale Jack , Kim Yongcheol , Niccoli Giampaolo , Tanjeko Ajime Tom , Serré Jef , Hazell Georgina , Sala Newby Graciela , Wang Ping , Johnson Jason L , Humphries Martin J , Gayan-Ramirez Ghislaine , Libby Peter , Crea Filippo , Degens Hans , Gijsen Frank , Johnson Thomas , Keshmiri Amir , Alexander Yvonne , Newby Andrew C , White Stephen J 
Published: February 2019

AbstractEndothelial erosion of atherosclerotic plaques and resulting thrombosis causes approximately 30% of acute coronary syndromes (ACS). As changes in the haemodynamic environment strongly influence endothelial function and contribute to plaque development, we reconstructed the coronary artery geometries of plaques with thrombi overlying intact fibrous caps from 17 ACS patients and performed computational fluid dynamic analysis. The results demonstrated that erosions frequently occur within areas of stenosis exposed to elevated flow. We recapitulated this flow environment in vitro, exposing human coronary artery endothelial cells to elevated flow and modelled smoking (a risk factor for erosion) by exposure to a combination of aqueous cigarette smoke extract and TNFα. This treatment induced endothelial detachment, which increased with pharmacological activation of the antioxidant system controlled by transcription factor Nrf2 (encoded by NFE2L2). The expression of Oxidative Stress Growth INhibitor genes OSGIN1 and OSGIN2 increased under these conditions and also in the aortas of mice exposed to cigarette smoke. Sustained high level expression of OSGIN1+2 resulted in cell cycle arrest, induction of senescence, loss of focal adhesions and actin stress fibres, and dysregulation of autophagy. Overexpression of either Nrf2 or OSGIN1+2 induced cell detachment, which did not depend on apoptosis, and could be partially rescued by inhibition of HSP70 using VER-155008, or AMP kinase activation using metformin. These findings demonstrate that under elevated flow, smoking-induced hyperactivation of Nrf2 can trigger endothelial cell detachment, highlighting a novel mechanism that could contribute to ACS involving endothelial erosion overlying stenotic plaques.
Non-coding Somatic Mutations Converge on the PAX8 Pathway in Epithelial Ovarian Cancer
Authors: Corona Rosario I. , Seo Ji-Heui , Lin Xianzhi , Hazelett Dennis J. , Reddy Jessica , Abassi Forough , Lin Yvonne G. , Mhawech-Fauceglia Paulette Y. , Lester Jenny , Shah Sohrab P. , Huntsman David G. , Gusev Alexander , Karlan Beth Y. , Berman Benjamin P. , Freedman Matthew L. , Gayther Simon A. , Lawrenson Kate 
Published: February 2019

ABSTRACTTranscriptional regulation is highly disease and cell-type specific. We performed H3K27ac chromatin immunoprecipitation and transcriptomic sequencing in primary tumors for the four different subtypes of invasive epithelial ovarian cancer (OC). Histotype-specific regulatory elements (REs) were enriched in enhancers (P<0.001).In silicoprediction of putative target genes for histotype-specific REs identified genes (WFDC2, P=5.5×10-5) and pathways (PI3K-Akt signaling, P<0.002) known to be involved in OC development. Some genes (e.g.PAX8andCA125) are associated with super-enhancers (SEs) in all OCs, while others are histotype-specific, includingPPP1R3Bwhich is associated with SEs specific to clear cell OC. Integrated analysis of active chromatin landscapes with somatic single nucleotide variants (SNVs) from whole genome sequencing (WGS) of 232 primary OCs identified frequently mutated REs, including theKLF6promoter (P=8.2×10-8) and a putative enhancer at chromosome 6p22.1 (P<0.05). In high-grade serous OCs, somatic SNVs clustered in binding sites for the PAX8 binding partner TEAD4 (P=6×10-11), while the collection ofcisregulatory elements associated withPAX8was the most frequently mutated set of enhancers in OC (P=0.003). Functional analyses supported our findings: Knockdown ofPPP1R3Bin clear cell OC cells significantly reduced intracellular glycogen content, a signature feature of this histotype; and stable knockout of a 635 bp region in the 6p22.1 enhancer induced downregulation of two predicted target genes,ZSCAN16andZSCAN12(P=6.6 x 10-4and P=0.02). In summary, we have characterized histotype-specific epigenomic and transcriptomic landscapes in OC and defined likely functional REs based on somatic mutation analysis of ovarian tumors.
Evidence accumulation during perceptual decision-making is sensitive to the dynamics of attentional selection
Authors: Rangelov Dragan , Mattingley Jason B. 
Published: February 2019

AbstractThe ability to select and combine multiple sensory inputs in support of accurate decisions is a hallmark of adaptive behaviour. Attentional selection is often needed to prioritize stimuli that are task-relevant and to attenuate potentially distracting sources of sensory information. As most studies of perceptual decision-making to date have made use of task-relevant stimuli only, relatively little is known about how attention modulates decision making. To address this issue, we developed a novel ‘integrated’ decision-making task, in which participants judged the average direction of successive target motion signals while ignoring concurrent and spatially overlapping distractor motion signals. In two experiments that varied the role of attentional selection, we used linear regression to quantify the influence of target and distractor stimuli on behaviour. Using electroencephalography, we characterised the neural correlates of decision making, attentional selection and feature-specific responses to target and distractor signals. While targets strongly influenced perceptual decisions and associated neural activity, we also found that concurrent and spatially coincident distractors exerted a measurable bias on both behaviour and brain activity. Our findings suggest that attention operates as a real-time but imperfect filter during perceptual decision-making by dynamically modulating the contributions of task-relevant and irrelevant sensory inputs.
Millefy: visualizing cell-to-cell heterogeneity in read coverage of single-cell RNA sequencing datasets
Authors: Ozaki Haruka , Hayashi Tetsutaro , Umeda Mana , Nikaido Itoshi 
Published: February 2019

AbstractBackgroundRead coverage of RNA sequencing data reflects gene expression and RNA processing events. Single-cell RNA sequencing (scRNA-seq) methods, particularly “full-length” ones, provide read coverage of many individual cells and have the potential to reveal cellular heterogeneity in RNA transcription and processing. However, visualization tools suited to highlighting cell-to-cell heterogeneity in read coverage are still lacking.ResultsHere, we have developed Millefy, a tool for visualizing read coverage of scRNA-seq data in genomic contexts. Millefy is designed to show read coverage of all individual cells at once in genomic contexts and to highlight cell-to-cell heterogeneity in read coverage. By visualizing read coverage of all cells as a heat map and dynamically reordering cells based on diffusion maps, Millefy facilitates discovery of “local” region-specific, cell-to-cell heterogeneity in read coverage, including variability of transcribed regions.ConclusionsMillefy simplifies the examination of cellular heterogeneity in RNA transcription and processing events using scRNA-seq data. Millefy is available as an R package (https://github.com/yuifu/millefy) and a Docker image to help use Millefy on the Jupyter notebook (https://hub.docker.com/r/yuifu/datascience-notebook-millefy).
Mechanical activation of TRPV4 channels controls albumin reabsorption by proximal tubule cells
Authors: Gualdani Roberta , Seghers François , Yerna Xavier , Schakman Olivier , Tajeddine Nicolas , Achouri Younès , Tissir Fadel , Devuyst Olivier , Gailly Philippe 
Published: February 2019

AbstractThe proximal tubule (PT) mediates the endocytosis of essential substances filtered through the glomerulus, including albumin and a large variety of low molecular weight proteins that would otherwise be lost in urine. Variations in the amount of ultrafiltrate delivered to the PT modulate protein endocytosis. Here we show that TRPV4 ion channel is expressed at the basolateral side of PT cells. Mechanical activation of TRPV4 by cell stretching induces an entry of Ca2+into the cytosol, which promotes endocytosis.Trpv4−/-mice present only a mild PT dysfunction in basal conditions but they exhibit a much more severe proteinuria thanTrpv4+/+mice when the permeability of glomerular filter is altered by systemic delivery of angiotensin II or antibodies against the glomerular basement membrane. These results emphasize the importance of TRPV4 channel in PT pressure sensing and provide insights into the mechanisms controlling protein reabsorption and potential targets for treating tubular proteinuria.SummaryThe proximal tubule (PT) mediates the endocytosis of albumin and low molecular weight proteins. Gualdani et al. report that variations in the amount of ultrafiltrate delivered to the PT activate TRPV4 ion channel expressed at the basolateral side of PT cells, which modulates protein endocytosis.
Trajectory of brain maturation in adolescent individuals at familial risk of mood disorder
Authors: de Nooij Laura , Harris Mathew A. , Hawkins Emma L. , Shen Xueyi , Clarke Toni-Kim , Chan Stella W.Y. , Ziermans Tim B. , McIntosh Andrew M. , Whalley Heather C. 
Published: February 2019

AbstractBackgroundAccelerated biological ageing has been proposed as a mechanism underlying mood disorder, but has been predominantly studied cross-sectionally in adult populations. It remains unclear whether differential ageing/maturation trajectories emerge earlier in life, in particular during the neurodevelopmental period of adolescence, and whether they are associated with onset of mood disorder and/or presence of familial risk.MethodsParticipants were young individuals (16-25 years) from the prospective longitudinal Scottish Bipolar Family Study (SBFS) with and without family history of mood disorder. All were well at time of recruitment. Implementing a structural MRI-based brain age prediction model, individual maturational trajectories were captured by the difference between predicted brain age and chronological age (brain-PAD) at baseline and two-year follow-up. Based on clinical assessment at follow-up, individuals were categorised into three groups: (i) controls who remained well (C-well,n=94), (ii) high familial risk who remained well (HR-well,n=73) and (iii) high familial risk who developed a mood disorder (HR-MD,n=38).ResultsResults showed no differences in brain-PAD between groups at baseline or follow-up. However, we found negative trajectories of brain-PAD for HR-MD versus C-well (β= −0.68 years,p<.001) and versus HR-well (β= −0.38 years,p=.01), and for HR-well versus C-well (β= −0.30 years,p=.03).ConclusionsThese findings suggest that within young individuals, onset of mood disorder and familial risk may be associated with a deceleration in brain maturation trajectory. However, without significantly differential status of brain maturation at follow-up, extended longitudinal research will need to show whether this marks the emergence of maturational lag.
Restriction enzymes use a 24 dimensional coding space to recognize 6 base long DNA sequences
Authors: Schneider Thomas D. , Jejjala Vishnu 
Published: February 2019

AbstractRestriction enzymes recognize and bind to specific sequences on invading bacteriophage DNA. Like a key in a lock, these proteins require many contacts to specify the correct DNA sequence. Using information theory we develop an equation that defines the number of independent contacts, which is the dimensionality of the binding. We show that EcoRI, which binds to the sequence GAATTC, functions in 24 dimensions. Information theory represents messages as spheres in high dimensional spaces. Better sphere packing leads to better communications systems. The densest known packing of hyperspheres occurs on the Leech lattice in 24 dimensions. We suggest that the single protein EcoRI molecule employs a Leech lattice in its operation. Optimizing density of sphere packing explains why 6 base restriction enzymes are so common.
Assessing graph-based read mappers against a novel baseline approach highlights strengths and weaknesses of the current generation of methods
Authors: Grytten Ivar , Rand Knut D. , Nederbragt Alexander J. , Sandve Geir K. 
Published: February 2019

AbstractGraph-based reference genomes have become popular as they allow read mapping and follow-up analyses in settings where the exact haplotypes underlying a high-throughput sequencing experiment are not precisely known. Two recent papers show that mapping to graph-based reference genomes can improve accuracy as compared to methods using linear references. Both of these methods index the sequences for most paths up to a certain length in the graph in order to enable direct mapping of reads containing common variants. However, the combinatorial explosion of possible paths through nearby variants also leads to a huge search space and an increased chance of false positive alignments to highly variable regions.We here assess two prominent graph-based read mappers against a novel hybrid baseline approach that combines an initial path determination with a tuned linear read mapping method. We show, using a previously proposed benchmark, that this simple approach is able to improve accuracy of read-mapping to graph-based reference genomes.Our method is implemented in a tool, Two-step Graph Mapper, which is available at https://github.com/uio-bmi/two_step_graph_mapper along with data and scripts for reproducing the experiments.
Pleiotropic effects ofebonyandtanon pigmentation and cuticular hydrocarbon composition inDrosophila melanogaster
Authors: Massey J. H. , Akiyama N. , Bien T. , Dreisewerd K. , Wittkopp P. J. , Yew J.Y. , Takahashi A. 
Published: February 2019

AbstractPleiotropic genes are genes that affect more than one trait. For example, many genes required for pigmentation in the fruit flyDrosophila melanogasteralso affect traits such as circadian rhythms, vision, and mating behavior. Here, we present evidence that two pigmentation genes,ebonyandtan, which encode enzymes catalyzing reciprocal reactions in the melanin biosynthesis pathway, also affect cuticular hydrocarbon (CHC) composition inD. melanogasterfemales. More specifically, we report thatebonyloss-of-function mutants have a CHC profile that is biased toward long (>25C) chain CHCs, whereastanloss-of-function mutants have a CHC profile that is biased toward short (<25C) chain CHCs. Moreover, pharmacological inhibition of dopamine synthesis, a key step in the melanin synthesis pathway, reversed the changes in CHC composition seen inebonymutants, making the CHC profiles similar to those seen intanmutants. These observations suggest that genetic variation affectingebonyand/ortanactivity might cause correlated changes in pigmentation and CHC composition in natural populations. We tested this possibility using theDrosophilaGenetic Reference Panel (DGRP) and found that CHC composition covaried with pigmentation as well as levels ofebonyandtanexpression in newly eclosed adults in a manner consistent with theebonyandtanmutant phenotypes. These data suggest that the pleiotropic effects ofebonyandtanmight contribute to covariation of pigmentation and CHC profiles inDrosophila.