bluuebunny/crossref_metadata_2025_split huggingface dataset:
Experimental design for large scale omic studies
Authors: Ogut Funda , Newman Jeremy R.B. , Bacher Rhonda , Concannon Patrick J. , Verhoeven Koen J.F. , McIntyre Lauren M. 
Published: January 2019

AbstractMolecular phenotyping has expanded from small sample sizes to larger complex studies and are now a common element in genetic studies. When large scale studies add a molecular phenotyping component, balancing omics batches for the factors of interest (e.g. treatment), regardless of the initial sample collection strategy always improves power. Where possible, confounding sources of experimental error that are not of interest (sample collection blocks and data collection plates) improves power as does planning batches for molecular phenotyping based on constraints during initial sample collection. Power for testing differences in molecular phenotypes is always higher when accounting for the entire experimental design during modeling. The inclusion of metadata that tracks sources variation is critical to our shared goals of enabling reproducible research.
Cost of preterm birth during initial hospitalization: A care provider’s perspective
Authors: Zainal Hadzri , Dahlui Maznah , Soelar Shahrul Aiman , Su Tin Tin 
Published: January 2019

ABSTRACTPreterm birth incidence has risen globally and remains a major cause of neonatal mortality despite improved survival. The demand and cost of initial hospitalization has also increased. This study assessed care provider cost in neonatal intensive care units of two hospitals in the state of Kedah, Malaysia. It utilized universal sampling and prospectively followed up preterm infants till discharge. Care provider cost was assessed using mixed method of top down approach and activity based costing. A total of 112 preterm infants were recruited from intensive care (93 infants) and minimal care (19 infants). Majority were from the moderate (23%) and late (36%) preterm groups followed by very preterm (32%) and extreme preterm (9%). Mean total cost per infant increased with level of care and degree of prematurity from MYR 2,751 (MYR 374 - MYR 10,103) for preterm minimal care, MYR 8,478 (MYR 817 - MYR 47,354) for late preterm intensive care to MYR 41,598 (MYR 25,351- MYR 58,828) for extreme preterm intensive care. Mean cost per infant per day increased from MYR 401 (MYR 363- MYR 534), MYR 444 (MYR 354 – MYR 916) to MYR 532 (MYR 443-MYR 939) respectively. Cost was dominated by overhead (fixed) costs for general (hospital), intermediate (clinical support services) and final (NICU) cost centers where it constituted at least three quarters of mean admission cost per infant while the remainder was consumables (variable) costs. Breakdown of overhead cost showed NICU specific overhead contributing at least two thirds of mean admission cost per infant. Personnel salary made up three quarters of NICU specific overhead. Laboratory investigation was the cost driver for consumables ranging from 29% (intensive care) to 84% (minimal care) of mean total consumables cost per infant. Gender, birth weight and length of stay were significant factors and cost prediction was developed with these variables.
Splice donor site sgRNAs enhance CRISPR/Cas9-mediated knockout efficiency
Authors: García-Tuñón Ignacio , Alonso-Pérez Verónica , Vuelta Elena , Pérez-Ramos Sandra , Herrero María , Méndez Lucía , Hernández-Sánchez Jesús María , Martín-Izquierdo Marta , Saldaña Raquel , Sevilla Julián , Sánchez-Guijo Fermín , Hernández-Rivas Jesús María , Sánchez-Martín Manuel 
Published: January 2019

ABSTRACTCRISPR/Cas9 enables the generation of knockout cell lines and null zygotes by inducing site-specific double-stranded breaks. In most cases the DSB is repaired by non-homologous end joining, resulting in small nucleotide insertions or deletions that can be used to construct knockout alleles. However, these mutations do not produce the desired null result in all cases, but instead generate a similar, functionally active protein. This effect could limit the therapeutic efficiency of gene therapy strategies based on abrogating oncogene expression, and therefore needs to be considered carefully. If there is an acceptable degree of efficiency of CRISPR/Cas9 delivery to cells, the key step for success lies in the effectiveness of a specific sgRNA at knocking out the oncogene, when only one sgRNA can be used. This study shows that the null effect could be increased with an sgRNA targeting the splice donor site (SDS) of the chosen exon. Following this strategy, the generation of null alleles would be facilitated in two independent ways: the probability of producing a frameshift mutation and the probability of interrupting the canonical mechanism of pre-mRNA splicing. In these contexts, we propose to improve the loss-of-function yield driving the CRISPR system at the SDS of critical exons.
Applying stochastic spike train theory for high-accuracy MEG/EEG
Authors: Haumann Niels Trusbak , Huotilainen Minna , Vuust Peter , Brattico Elvira 
Published: January 2019

AbstractThe accuracy of electroencephalography (EEG) and magnetoencephalography (MEG) is challenged by overlapping sources from within the brain. This lack of accuracy is a severe limitation to the possibilities and reliability of modern stimulation protocols in basic research and clinical diagnostics. As a solution, we here introduce a theory of stochastic neuronal spike timing probability densities for describing the large-scale spiking activity in neural networks, and a novel spike density component analysis (SCA) method for isolating specific neural sources. Three studies are conducted based on 564 cases of evoked responses to auditory stimuli from 94 human subjects each measured with 60 EEG electrodes and 306 MEG sensors. In the first study we show that the large-scale spike timing (but not non-encephalographic artifacts) in MEG/EEG waveforms can be modeled with Gaussian probability density functions with high accuracy (median 99.7%-99.9% variance explained), while gamma and sine functions fail describing the MEG and EEG waveforms. In the second study we confirm that SCA can isolate a specific evoked response of interest. Our findings indicate that the mismatch negativity (MMN) response is accurately isolated with SCA, while principal component analysis (PCA) fails supressing interference from overlapping brain activity, e.g. from P3a and alpha waves, and independent component analysis (ICA) distorts the evoked response. Finally, we confirm that SCA accurately reveals inter-individual variation in evoked brain responses, by replicating findings relating individual traits with MMN variations. The findings of this paper suggest that the commonly overlapping neural sources in single-subject or patient data can be more accurately separated by applying the introduced theory of large-scale spike timing and method of SCA in comparison to PCA and ICA.Significance statementElectroencephalography (EEG) and magnetoencelopraphy (MEG) are among the most applied non-invasive brain recording methods in humans. They are the only methods to measure brain function directly and in time resolutions smaller than seconds. However, in modern research and clinical diagnostics the brain responses of interest cannot be isolated, because of interfering signals of other ongoing brain activity. For the first time, we introduce a theory and method for mathematically describing and isolating overlapping brain signals, which are based on prior intracranial in vivo research on brain cells in monkey and human neural networks. Three studies mutually support our theory and suggest that a new level of accuracy in MEG/EEG can achieved by applying the procedures presented in this paper.
How many cubs can a mum raise? Maternal age and size influence litter size in polar bears
Authors: Folio Dorinda Marie , Aars Jon , Gimenez Olivier , Derocher Andrew E. , Wiig Øystein , Cubaynes Sarah 
Published: January 2019

AbstractLife history theory predicts that females’ age and size affect the level of maternal investment in current reproduction, balanced against future reproductive effort, maintenance and survival. Using long-term (30 years) individual data on 231 female polar bears (Ursus maritimus), we assessed age- and size-specific variation on litter size. Litter size varied with maternal age, younger females had higher chances of losing a cub during their first months of life. Results suggest an improvement of breeding abilities early in life due to experience with subsequent reproductive senescence. Litter size increased with maternal size, indicating that size may reflect individual quality. Heterogeneity was observed among the largest females, suggesting that large size comes at a cost. Maternal traits and environmental conditions may act together to influence reproductive success.
Individual Tree-Crown Detection in RGB Imagery Using Semi-Supervised Deep Learning Neural Networks
Authors: Weinstein Ben G. , Marconi Sergio , Bohlman Stephanie , Zare Alina , White Ethan 
Published: January 2019

AbstractRemote sensing can transform the speed, scale, and cost of biodiversity and forestry surveys. Data acquisition currently outpaces the ability to identify individual organisms in high resolution imagery. We outline an approach for identifying tree-crowns in RGB imagery while using a semi-supervised deep learning detection network. Individual crown delineation has been a long-standing challenge in remote sensing and available algorithms produce mixed results. We show that deep learning models can leverage existing Light Detection and Ranging (LIDAR)-based unsupervised delineation to generate trees that are used for training an initial RGB crown detection model. Despite limitations in the original unsupervised detection approach, this noisy training data may contain information from which the neural network can learn initial tree features. We then refine the initial model using a small number of higher-quality hand-annotated RGB images. We validate our proposed approach while using an open-canopy site in the National Ecological Observation Network. Our results show that a model using 434,551 self-generated trees with the addition of 2848 hand-annotated trees yields accurate predictions in natural landscapes. Using an intersection-over-union threshold of 0.5, the full model had an average tree crown recall of 0.69, with a precision of 0.61 for the visually-annotated data. The model had an average tree detection rate of 0.82 for the field collected stems. The addition of a small number of hand-annotated trees improved the performance over the initial self-supervised model. This semi-supervised deep learning approach demonstrates that remote sensing can overcome a lack of labeled training data by generating noisy data for initial training using unsupervised methods and retraining the resulting models with high quality labeled data.
CADHERIN-11 BLOCKADE REDUCES INFLAMMATION-DRIVEN FIBROTIC REMODELING AND IMPROVES OUTCOMES AFTER MYOCARDIAL INFARCTION
Authors: Schroer Alison K. , Bersi Matthew R. , Clark Cynthia R. , Zhang Qinkun , Sanders Lehanna H. , Hatzopoulos Antonis K. , Force Thomas L. , Majka Susan M. , Lal Hind , Merryman W. David 
Published: January 2019

AbstractBackgroundOver one million Americans experience myocardial infarction (MI) every year, and the resulting scar and subsequent cardiac fibrosis contribute to heart failure and death. A specialized cell-cell adhesion protein, cadherin-11 (CDH11), contributes to inflammation and fibrosis in rheumatoid arthritis, pulmonary fibrosis, and aortic valve calcification but has not yet been studied in the context of cardiac remodeling after MI. We hypothesized that targeting CDH11 function after MI would reduce inflammation-driven fibrotic remodeling and infarct expansion to improve functional outcomes in mice.MethodsMI was induced by ligation of the left anterior descending artery in transgenic mice with reduced or ablated CDH11, wild type mice receiving bone marrow transplants fromCdh11transgenic animals, and wild type mice treated with a functional blocking antibody against CDH11 (SYN0012). Cardiac function was measured by echocardiography, expression of cell populations was quantified by flow cytometry, and tissue remodeling by altered histological assessment and transcription of inflammatory and pro-angiogenic genes by qPCR. Co-culture was used to assess interactions between cardiac fibroblasts and macrophages.ResultsMI increased transcription ofCdh11in non-cardiomyocyte cells. Mice with deletion ofCdh11and wild type mice receiving bone marrow transplants fromCdh11transgenic animals had improved cardiac function and dimensions after MI. Animals given SYN0012 had improved cardiac function, reduced tissue remodeling, and altered transcription of inflammatory and proangiogenic genes. Targeting CDH11 also reduced the number of bone marrow-derived myeloid cells and increased pro-angiogenic cells in the heart three days after MI, consistent with a decrease in transcription and expression of IL-6 in the infarct region. Cardiac fibroblast and macrophage interactions led to an increase in IL-6 secretion that was reduced with SYN0012 treatment in vitro.ConclusionsOur findings suggest that CDH11-expressing cells contribute to inflammation-driven fibrotic remodeling after MI, and that targeting CDH11 with a blocking antibody improves cardiac function after MI. This improvement is likely mediated by altered recruitment of bone marrow-derived cells, thereby limiting the macrophage-induced expression of IL-6 by fibroblasts and promoting vascularization.
Novel IRE1-dependent proinflammatory signaling controls tumor infiltration by myeloid cells
Authors: Obacz Joanna , Archambeau Jérôme , Sicari Daria , Le Reste Pierre Jean , Pineau Raphael , Martin Sophie , Barroso Kim , Vlachavas Efstathios , Voutetakis Konstantinos , Fainsod-Levi Tanya , Obiedat Akram , Granot Zvi , Tirosh Boaz , Samal Juhi , Pandit Abhay , Patterson John , Zheng Qinping , Négroni Luc , Chatziioannou Aristotelis , Quillien Véronique , Avril Tony , Chevet Eric 
Published: January 2019

AbstractTumor cells are exposed to intrinsic and environmental challenges that trigger endoplasmic reticulum (ER) homeostasis alteration, in turn leading to ER stress. To cope with this, tumor cells engage an adaptive signaling pathway, the unfolded protein response (UPR) thus promoting the acquisition of malignant features. As such, glioblastoma multiforme (GBM), the most aggressive primary brain tumors, exhibit constitutive UPR signals to sustain growth. Herein, we showed that signaling elicited by one of the UPR sensors, IRE1, promotes GBM tumor invasion, angiogenesis and infiltration by macrophages. Hence, high IRE1 activity in tumors predicts worse outcome. We further dissect IRE1-dependent mechanisms that shape the brain tumor immune microenvironment towards myeloid cells. We identify an IRE1-dependent signaling pathway that directly controls the expression/release of proinflammatory chemokines (CXCL2, IL6, IL8) leading to tumor cell-mediated chemoattraction of neutrophils and macrophages. This pathway requires XBP1 non-conventional mRNA splicing and XBP1s-dependent expression of the E2 ubiquitin enzyme UBE2D3. The latter contributes to the degradation of the NFκB inhibitor IκB, leading to the up-regulation of proinflammatory chemokines. Our work identifies a novel IRE1/UBE2D3 proinflammatory signaling axis instrumental to pro-tumoral immune regulation of GBM.
Phosphatidylinositol 3,5-Bisphosphate regulates Ca2+Transport During Yeast Vacuolar Fusion through Activation of the Ca2+ATPase Pmc1
Authors: Miner Gregory E. , Sullivan Katherine D. , Guo Annie , Starr Matthew L. , Ellis EZ C. , Jones Brandon C. , Fratti Rutilio A. 
Published: January 2019

ABSTRACTThe transport of Ca2+across membranes precedes the fusion and fission of various lipid bilayers. Yeast vacuoles during hyperosmotic shock become fragmented through fission events that require Ca2+efflux of their luminal stores through the TRP channel Yvc1. This requires the production of the lipid PI(3,5)P2by Fab1. Ca2+is also released during vacuole fusion upontrans-SNARE complex assembly, however, the role of PI(3,5)P2remains unclear. Here we demonstrate that elevated PI(3,5)P2levels abolish Ca2+efflux during fusion, indicating that PI(3,5)P2has opposing effects on Ca2+transport in fission versus fusion. Notably, Ca2+efflux was enhanced when PI(3,5)P2levels were reduced. Importantly, the effect of PI(3,5)P2on Ca2+flux was independent of Yvc1. Rather, the effect was dependent on the Ca2+pump Pmc1. Vacuoles lacking Pmc1 were resistant to the effects of PI(3,5)P2, while those lacking Yvc1 remained sensitive. Furthermore altering PI(3,5)P2levels affects the interactions of Pmc1 with the Vocomponent Vph1 and the R-SNARE Nyv1. We now propose a model in which elevated PI(3,5)P2activates continued Pmc1 function to prevent the accumulation of released extraluminal Ca2+.SummaryDuring osmotic stress PI(3,5)P2triggers Ca2+release from vacuoles. Here we show PI(3,5)P2stimulates Ca2+uptake by vacuoles during fusion, illustrating that it has a dual role in Ca2+transport.
N-terminal 45 amino acids of DEF6 are necessary and sufficient to spontaneously colocalise with DCP1 in P-bodies
Authors: Cheng Huaitao , Alsayegh Maha , Sablitzky Fred 
Published: January 2019

ABSTRACTDEF6 (Differentially Expressed in FDCP 6, also known as IBP and/or SLAT) is critical for the development of autoimmune disease and cancer. In T cells, DEF6 participates in TCR-mediated signalling determining T helper cell-mediated immune responses. In addition, DEF6 acts as a guanine nucleotide exchange factor (GEF) for Rho GTPases facilitating F-actin assembly and stabilisation of the immunological synapse (IS). However, DEF6 is also a component of mRNA processing bodies (P-bodies) linking it to mRNA metabolism. Including DEF6, more than 34 proteins have been shown to localise in P-bodies many of which contain a coiled coil domain, a super-secondary structure likely to facilitate interaction between these proteins. Accordingly, we suggested that the coiled coil domain in the C-terminal end of DEF6 was mediating P-body localisation of DEF6 under cellular stress conditions. However, a comprehensive analysis of wild type and mutant DEF6 proteins expressed in COS7 cells revealed that the coiled coil domain is dispensable for P-body colocalisation. Instead, we show here that the N-terminal 45 amino acids of DEF6 that contain one Ca2+-binding EF hand motif are sufficient to target DEF6 to P-bodies whereas the N-terminal 30 amino acids containing a disrupted EF hand motif are insufficient.
Impoverished auditory cues fail to engage brain networks controlling spatial selective attention
Authors: Deng Yuqi , Choi Inyong , Shinn-Cunningham Barbara , Baumgartner Robert 
Published: January 2019

AbstractSpatial selective attention enables listeners to process a signal of interest in natural settings. However, most past studies on auditory spatial attention used impoverished spatial cues: presenting competing sounds to different ears, using only interaural differences in time (ITDs) and/or intensity (IIDs), or using non-individualized head-related transfer functions (HRTFs). Here we tested the hypothesis that impoverished spatial cues impair spatial auditory attention by only weakly engaging relevant cortical networks. Eighteen normal-hearing listeners reported the content of one of two competing syllable streams simulated at roughly +30 ° and −30° azimuth. The competing streams consisted of syllables from two different-sex talkers. Spatialization was based on natural spatial cues (individualized HRTFs), individualized IIDs, or generic ITDs. We measured behavioral performance as well as electroencephalographic markers of selective attention. Behaviorally, subjects recalled target streams most accurately with natural cues. Neurally, spatial attention significantly modulated early evoked sensory response magnitudes only for natural cues, not in conditions using only ITDs or IIDs. Consistent with this, parietal oscillatory power in the alpha band (8-14 Hz; associated with filtering out distracting events from unattended directions) showed significantly less attentional modulation with isolated spatial cues than with natural cues. Our findings support the hypothesis that spatial selective attention networks are only partially engaged by impoverished spatial auditory cues. These results not only suggest that studies using unnatural spatial cues underestimate the neural effects of spatial auditory attention, they also illustrate the importance of preserving natural spatial cues in assistive listening devices to support robust attentional control.
Structural basis for the recognition of K48-linked Ub chain by proteasomal receptor Rpn13
Authors: Liu Zhu , Dong Xu , Yi Hua-Wei , Yang Ju , Gong Zhou , Wang Yi , Liu Kan , Zhang Wei-Ping , Tang Chun 
Published: January 2019

ABSTRACTThe interaction between K48-linked ubiquitin (Ub) chain and Rpn13 is important for proteasomal degradation of ubiquitinated substrate proteins. Only the complex structure between the N-terminal domain of Rpn13 (Rpn13NTD) and Ub monomer has been characterized, and it remains unclear how Rpn13 specifically recognizes K48-linked Ub chain. Using single-molecule FRET, here we show that K48-linked diubiquitin (K48-diUb) fluctuates among three distinct conformational states, and a preexisting compact state is selectively enriched by Rpn13NTD. The same binding mode is observed for full-length Rpn13 and longer K48-linked Ub chain. Using solution NMR spectroscopy, we have solved the complex structure between Rpn13NTDand K48-diUb. In the structure, Rpn13NTDsimultaneously interacts with proximal and distal Ub subunits of K48-diUb that remain associated in the complex, thus corroborating smFRET findings. The proximal Ub interacts with Rpn13NTDsimilarly as the Ub monomer in the known Rpn13NTD:Ub structure, while the distal Ub binds to a largely electrostatic surface of Rpn13NTD. Thus, a charge reversal mutation in Rpn13NTDcan weaken the interaction between Rpn13 and K48-linked Ub chain, causing accumulation of ubiquitinated proteins. Moreover, blockage of the access of the distal Ub to Rpn13NTDwith a proximity attached Ub monomer can also disrupt the interaction between Rpn13 and K48-diUb. Together, the bivalent interaction of K48-linked Ub chain with Rpn13 provides the structural basis for Rpn13 linkage selectivity, which opens a new window for modulating proteasomal function.