bluuebunny/crossref_metadata_2025_split huggingface dataset:
Predicting Residual Function in Hemodialysis and Hemodiafiltration – A Population Kinetic, Decision Analytic Approach
Authors: Achakzai Mohammad I , Argyropoulos Christos , Roumelioti Maria-Eleni 
Published: July 2019

AbstractIn this study, we introduce a novel framework for the estimation of residual renal function (RRF), based on the population compartmental kinetic behavior of Beta 2 Microglobulin (B2M) and its dialytic removal. Using this model, we simulated a large cohort of patients with various levels of RRF receiving either conventional high-flux hemodialysis or on-line hemodiafiltration. These simulations were used to estimate a novel population kinetic (PK) equation for RRF (PK-RRF) that was validated in an external public dataset of real patients. We assessed the performance of the resulting equation(s) against their ability to estimate urea clearance using cross-validation. Our equations derived entirely from computer simulations and advanced statistical modeling, and had extremely high discrimination (AUC 0.888 – 0.909) when applied to a human dataset of measurements of RRF. A clearance-based equation that utilized pre and post dialysis B2M measurements, patient weight, treatment duration and ultrafiltration had higher discrimination than an equation previously derived in humans. Furthermore, the derived equations appeared to have higher clinical usefulness as assessed by Decision Curve Analysis, potentially supporting decisions that for individualizing dialysis frequency in patients with preserved RRF.
Quantifying the RNA cap epitranscriptome reveals novel caps in cellular and viral RNA
Authors: Wang Jin , Chew Bing Liang Alvin , Lai Yong , Dong Hongping , Xu Luang , Balamkundu Seetharamsingh , Cai Weiling Maggie , Cui Liang , Liu Chuan Fa , Fu Xin-Yuan , Lin Zhenguo , Shi Pei-Yong , Lu Timothy K. , Luo Dahai , Jaffrey Samie R. , Dedon Peter C. 
Published: July 2019

ABSTRACTChemical modification of transcripts with 5’ caps occurs in all organisms. Here we report a systems-level mass spectrometry-based technique, CapQuant, for quantitative analysis of the cap epitranscriptome in any organism. The method was piloted with 21 canonical caps – m7GpppN, m7GpppNm, GpppN, GpppNm, and m2,2,7GpppG – and 5 “metabolite” caps – NAD, FAD, UDP-Glc, UDP-GlcNAc, and dpCoA. Applying CapQuant to RNA from purified dengue virus,Escherichia coli, yeast, mice, and humans, we discovered four new cap structures in humans and mice (FAD, UDP-Glc, UDP-GlcNAc, and m7Gpppm6A), cell- and tissue-specific variations in cap methylation, and surprisingly high proportions of caps lacking 2’-O-methylation, such as m7Gpppm6A in mammals and m7GpppA in dengue virus, and we did not detect cap m1A/m1Am in humans. CapQuant accurately captured the preference for purine nucleotides at eukaryotic transcription start sites and the correlation between metabolite levels and metabolite caps. The mystery around cap m1A/m1Am analysis remains unresolved.
Single Photon, Time-Gated, Phasor-based Fluorescence Lifetime Imaging Through Highly Scattering Medium
Authors: Ankri Rinat , Basu Arkaprabha , Ulku Arin Can , Bruschini Claudio , Charbon Edoardo , Weiss Shimon , Michalet Xavier 
Published: June 2019

AbstractFluorescence lifetime imaging (FLI) is a powerful tool forin vitroand non-invasivein vivobiomolecular and cellular investigations. Fluorescence lifetime is an intrinsic characteristic of any fluorescent dye which, to some extent, does not depend on excitation intensity and signal level. However, when usedin vivowith visible wavelength emitting fluorophores, FLI is complicated by (i) light scattering as well as absorption by tissues, which significantly reduces fluorescence intensity, (ii) tissue autofluorescence (AF), which decreases the signal to noise ratio and (iii) broadening of the decay signal, which can result in incorrect lifetime estimation. Here, we report the use of a large-frame time-gated single-photon avalanche diode (SPAD) imager,SwissSPAD2, with a very short acquisition time (in the milliseconds range) and a wide-field microscopy format. We use the phasor approach to convert each pixel’s data into its local lifetime. The phasor transformation provides a simple and fast visual method for lifetime imaging and is particularly suitable forin vivoFLI which suffers from deformation of the fluorescence decay, and makes lifetime extraction by standard fitting challenging. We show, for single dyes, that the phasor cloud distribution (of pixels) increases with decay broadening due to scattering and decreasing fluorescence intensity. Yet, as long as the fluorescence signal is higher than the tissue-like phantom AF, a distinct lifetime can still be clearly identified with an appropriate background correction. Lastly, we demonstrate the detection of few hundred thousand A459 cells expressing the fluorescent protein mCyRFP1 through highly scattering phantom layers, despite significant scattering and the presence of the phantom AF.
Aging is associated with a systemic length-driven transcriptome imbalance
Authors: Stoeger Thomas , Grant Rogan A. , McQuattie-Pimentel Alexandra C. , Anekalla Kishore , Liu Sophia S. , Tejedor-Navarro Heliodoro , Singer Benjamin D. , Abdala-Valencia Hiam , Schwake Michael , Tetreault Marie-Pier , Perlman Harris , Balch William E , Chandel Navdeep , Ridge Karen , Sznajder Jacob I. , Morimoto Richard I. , Misharin Alexander V. , Budinger G.R. Scott , Amaral Luis A. Nunes 
Published: July 2019

AbstractAging manifests itself through a decline in organismal homeostasis and a multitude of cellular and physiological functions1. Efforts to identify a common basis for vertebrate aging face many challenges; for example, while there have been documented changes in the expression of many hundreds of mRNAs, the results across tissues and species have been inconsistent2. We therefore analyzed age-resolved transcriptomic data from 17 mouse organs and 51 human organs using unsupervised machine learning3–5 to identify the architectural and regulatory characteristics most informative on the differential expression of genes with age. We report a hitherto unknown phenomenon, a systemic age-dependent length-driven transcriptome imbalance that for older organisms disrupts the homeostatic balance between short and long transcript molecules for mice, rats, killifishes, and humans. We also demonstrate that in a mouse model of healthy aging, length-driven transcriptome imbalance correlates with changes in expression of splicing factor proline and glutamine rich (Sfpq), which regulates transcriptional elongation according to gene length6. Furthermore, we demonstrate that length-driven transcriptome imbalance can be triggered by environmental hazards and pathogens. Our findings reinforce the picture of aging as a systemic homeostasis breakdown and suggest a promising explanation for why diverse insults affect multiple age-dependent phenotypes in a similar manner.
miR-1/206 down-regulates splicing factor Srsf9 to promote myogenesis
Authors: Bjorkman Kristen K. , Buvoli Massimo , Pugach Emily K. , Polmear Michael M. , Leinwand Leslie A. 
Published: July 2019

AbstractBackgroundMyogenesis is driven by specific changes in the transcriptome that occur during the different stages of muscle differentiation. In addition to controlled transcriptional transitions, several other post-transcriptional mechanisms direct muscle differentiation. Both alternative splicing and miRNA activity regulate gene expression and production of specialized protein isoforms. Importantly, disruption of either process often results in severe phenotypes as reported for several muscle diseases. Thus, broadening our understanding of the post-transcriptional pathways that operate in muscles will lay the foundation for future therapeutic interventions.MethodsWe employed bioinformatics analysis in concert with the well-established C2C12 cell system for predicting and validating novel miR-1 and miR-206 targets engaged in muscle differentiation. We used reporter gene assays to test direct miRNA targeting and studied C2C12 cells stably expressing one of the cDNA candidates fused to a heterologous, miRNA-resistant 3’ UTR. We monitored effects on differentiation by measuring fusion index, myotube area, and myogenic gene expression during time course differentiation experiments.ResultsGene ontology analysis revealed a strongly enriched set of putative miR-1 and miR-206 targets associated with RNA metabolism. Notably, the expression levels of several candidates decreased during C2C12 differentiation. We discovered that the splicing factor Srsf9 is a direct target of both miRNAs during myogenesis. Persistent Srsf9 expression during differentiation impaired myotube formation and blunted induction of the early pro-differentiation factor myogenin as well as the late differentiation marker sarcomeric myosin, Myh8.ConclusionsOur data uncover novel miR-1 and miR-206 cellular targets and establish a functional link between the splicing factor Srsf9 and myoblast differentiation. The finding that miRNA-mediated clearance of Srsf9 is a key myogenic event illustrates the coordinated and sophisticated interplay between the diverse components of the gene regulatory network.
A generalised approach to detect selected haplotype blocks in Evolve and Resequence experiments
Authors: Otte Kathrin A. , Schlötterer Christian 
Published: July 2019

AbstractShifting from the analysis of single nucleotide polymorphisms to the reconstruction of selected haplotypes greatly facilitates the interpretation of Evolve and Resequence (E&R) experiments. Merging highly correlated hitchhiker SNPs into haplotype blocks reduces thousands of candidates to few selected regions. Current methods of haplotype reconstruction from Pool-Seq data need a variety of data-specific parameters that are typically defined ad hoc and require haplotype sequences for validation. Here, we introduce haplovalidate, a tool which detects selected haplotypes in a broad range of Pool-seq time series data without the need of sequenced haplotypes. Haplovalidate makes data-driven choices of two key parameters for the clustering procedure, the minimum correlation between SNPs constituting a cluster and the window size. Applying haplovalidate to simulated and experimental E&R data reliably detects selected haplotype blocks with low false discovery rates – independent if few or many selection targets are included. Our analyses identified an important restriction of the haplotype block-based approach to describe the genomic architecture of adaptation. We detected a substantial fraction of haplotypes containing multiple selection targets. These blocks were considered as one region of selection and therefore led to under-estimation of the number of selection targets. We demonstrate that the separate analysis of earlier time points can significantly increase the separation of selection targets into individual haplotype blocks. We conclude that the analysis of selected haplotype blocks has a large potential for the characterisation of the adaptive architecture with E&R experiments.
Channeling macrophage polarization via selective translation inhibition by rocaglates increases macrophage resistance to Mycobacterium tuberculosis
Authors: Chatterjee Sujoy , Yabaji Shivraj M. , Bhattacharya Bidisha , Waligurski Emily , Vallavoju Nandini , Ray Somak , Brown Lauren E. , Beeler Aaron B. , Ivanov Alexander R. , Kobzik Lester , Porco John A. , Kramnik Igor 
Published: July 2019

AbstractMacrophages contribute to host immunity and tissue homeostasis via alternative activation programs. M1-like macrophages control intracellular bacterial pathogens and tumor progression. In contrast, M2-like macrophages shape reparative microenvironments that can be conducive for pathogen survival or tumor growth. An imbalance of these macrophages phenotypes may perpetuate sites of chronic unresolved inflammation, such as infectious granulomas and solid tumors.We have found that plant-derived and synthetic rocaglates sensitize macrophages to low concentrations of the M1-inducing cytokine IFN-gamma and inhibit their responsiveness to IL-4, a prototypical activator of the M2-like phenotype. Treatement of primary macrophages with rocaglates increased their resilience to oxidative stress, stimulated autophagy and killing of intracellular mycobacteria. Thus, rocaglates represent a novel class of immunomodulators that can direct macrophage polarization towards the M1-like phenotype in complex microenvironments associated with hypofunction of type 1 and/or hyperactivation of type 2 immunity, e.g. chronic bacterial infections, allergies and, possibly, certain tumors.
Genetic immunodeficiency and autoimmune disease reveal distinct roles of Hem1 in the WAVE2 and mTORC2 complexes
Authors: Comrie William A. , Poli M. Cecilia , Cook Sarah A. , Similuk Morgan , Oler Andrew J. , Faruqi Aiman J. , Kuhns Douglas B. , Yang Sheng , Carisey Alexandre F. , Fournier Benjamin , Anderson D. Eric , Price Susan , Chahla Wadih Abou , Vargas-Hernandez Alexander , Forbes Lisa R. , Mace Emily M. , Cao Tram N. , Coban-Akdemir Zeynep H. , Jhangiani Shalini N. , Muzny Donna M. , Gibbs Richard A. , Lupski James R. , Orange Jordan S. , Cuvelier Geoffrey D.E. , Hassani Moza Al , Kaabi Nawal AL , Yafei Zain Al , Jyonouchi Soma , Raje Nikita , Caldwell Jason W. , Huang Yanping , Burkhardt Janis K. , Latour Sylvain , Chen Baoyu , ElGhazali Gehad , Rao V. Koneti , Chinn Ivan K. , Lenardo Michael J. 
Published: July 2019

AbstractImmunodeficiency often coincides with immune hyperresponsiveness such as autoimmunity, lymphoproliferation, or atopy, but the molecular basis of this paradox is typically unknown. We describe four families with immunodeficiency coupled with atopy, lymphoproliferation, cytokine overproduction, hemophagocytic lymphohistocytosis, and autoimmunity. We discovered loss-of-function variants in the gene NCKAP1L, encoding the hematopoietic-specific Hem1 protein. Three mutations cause Hem1 protein and WAVE regulatory complex (WRC) loss, thereby disrupting actin polymerization, synapse formation, and immune cell migration. Another mutant, M371V encodes a stable Hem1 protein but abrogates binding of the Arf1 GTPase and identifies Arf1 as a critical Hem1 regulator. All mutations reduce the cortical actin barrier to cytokine release explaining immune hyperresponsiveness. Finally, Hem1 loss blocked mTORC2-dependent AKT phosphorylation, T cell proliferation, and effector cytokine production during T cell activation. Thus, our data show that Hem1 independently governs two key regulatory complexes, the WRC and mTORC2, and how Hem1 loss causes a combined immunodeficiency and immune hyperresponsiveness disease.One sentence summaryHem1 loss of function mutations cause a congenital immunodysregulatory disease and reveal its role regulating WAVE2 and mTORC2 signaling.
In vitro ribosome synthesis and evolution through ribosome display
Authors: Hammerling Michael J. , Fritz Brian R. , Yoesep Danielle J. , Kim Do Soon , Carlson Erik D. , Jewett Michael C. 
Published: July 2019

ABSTRACTDirected evolution of the ribosome for expanded substrate incorporation and novel functions is challenging because the requirement of cell viability limits the mutations that can be made. However, our recent development of an integrated strategy for the in vitro synthesis and assembly of translationally competent ribosomes (iSAT) enables the rapid generation of large libraries of ribosome variants in a cell-free environment. Here we combine the iSAT system with ribosome display to develop a fully in vitro methodology for ribosome synthesis and evolution (called RISE). We validate this method by selecting highly active genotypes which are resistant to the antibiotic clindamycin from a library of ribosome variants. We further demonstrate the prevalence of positive epistasis in successful genotypes, highlighting the importance of such interactions in selecting for new function. We anticipate that RISE will facilitate understanding of molecular translation and enable selection of ribosomes with altered properties.
A systems genomics approach to uncover patient-specific pathogenic pathways and proteins in a complex disease
Authors: Brooks Johanne , Modos Dezso , Sudhakar Padhmanand , Fazekas David , Zoufir Azedine , Kapuy Orsolya , Szalay-Beko Mate , Madgwick Matthew , Verstockt Bram , Hall Lindsay , Watson Alastair , Tremelling Mark , Parkes Miles , Vermeire Severine , Bender Andreas , Carding Simon R. , Korcsmaros Tamas 
Published: July 2019

AbstractWe describe a novel precision medicine workflow, the integrated single nucleotide polymorphism network platform (iSNP), designed to identify the exact mechanisms of how SNPs affect cellular regulatory networks, and how SNP co-occurrences contribute to disease pathogenesis in ulcerative colitis (UC). Using SNP profiles of 377 UC patients, we mapped the regulatory effects of the SNPs to a human signalling network containing protein-protein, miRNA-mRNA and transcription factor binding interactions. Unsupervised clustering algorithms grouped these patient-specific networks into four distinct clusters based on two large disease hubs, NFKB1 and PKCB. Pathway analysis identified the epigenetic modification as common and the T-cell specific responses as differing signalling pathways in the clusters. By integrating individual transcriptomes in active and quiescent disease setting to the patient networks, we validated the impact of non-coding SNPs. The iSNP approach identified regulatory effects of disease-associated non-coding SNPs, and identified how pathogenesis pathways are activated via different genetic modifications.
Free-energy-based framework for early forecasting of stem cell differentiation
Authors: Suresh H. , Shishvan S.S. , Vigliotti A. , Deshpande V.S. 
Published: July 2019

AbstractCommitment of stem cells to different lineages is inherently stochastic but regulated by a range of environmental bio/chemo/mechanical cues. Here we develop an integrated stochastic modelling framework for predicting the differentiation of hMSCs in response to a range of environmental cues including sizes of adhesive islands, stiffness of substrates and treatment with ROCK inhibitors in both growth and mixed media. The statistical framework analyses the fluctuations of cell morphologies over around a 24-hour period after seeding the cells in the specific environment and uses the distribution of their cytoskeletal free-energy to forecast the lineage the hMSCs will commit to. The cytoskeletal free-energy which succinctly parameterises the biochemical state of the cell is shown to capture hMSC commitment over a range of environments while simple morphological factors such as cell shape, tractions on their own are unable to correlate with lineages hMSCs adopt.
High density of white-faced capuchins (Cebus capucinus) and habitat quality in the Taboga Forest of Costa Rica
Authors: Johnson Elizabeth Tinsley , Benítez Marcela E. , Fuentes Alexander , McLean Celia R. , Norford Ariek B. , Ordoñez Juan Carlos , Beehner Jacinta C. , Bergman Thore J. 
Published: July 2019

ABSTRACTAcross the globe, primate species and habitats are threatened by human activity. This is especially true for species found in tropical dry forests, which are widely distributed and comprise diverse habitats that remain largely unprotected. Evidence suggests that some primate species endemic to tropical dry forests may be more sensitive to anthropogenic disturbance than others, but our ability to predict primate abundance in the face of disturbance also depends on the specific variables for each site. Here, we consider the factors that explain the high density of white-faced capuchins (Cebus capucinus) found in the Taboga Forest, Costa Rica, a relatively small fragment of tropical dry forest surrounded by agricultural fields. Our analyses suggest that, for capuchins (and potentially for mantled howler monkeys,Alouatta palliata), the size and disturbance of a forest fragment may matter less than the composition and availability of key resources, like above-ground water. Group sightings for both species were higher near permanent water sources, but group sightings did not vary between edge and interior forest. These findings help explain why some primate species can flourish even alongside anthropogenic disturbance and thus carry important implications for conservation efforts. Smaller forest fragments, like Taboga, may be able to support high densities of some species because they provide a mosaic of habitats and key resources that buffer adverse ecological conditions. Future studies will assess the extent to which primates in the Taboga Forest rely on the canals versus the river and will consider how the high density of capuchins in Taboga influences ranging patterns, home range overlap, and the frequency and intensity of intergroup encounters.RESEARCH HIGHLIGHTSHere we introduce a new white-faced capuchin study site in the Taboga Forest, Costa Rica, a fragmented tropical dry forest.Forest fragments like Taboga may support high primate densities because they provide a mosaic of habitats and key resources.
Voxel-to-voxel predictive models reveal unexpected structure in unexplained variance
Authors: Mell Maggie Mae , St-Yves Ghislain , Naselaris Thomas 
Published: July 2019

AbstractEncoding models based on deep convolutional neural networks (DCNN) more accurately predict BOLD responses to natural scenes in the visual system than any other currently available model. However, DCNN-based encoding models fail to predict a significant amount of variance in the activity of most voxels in all visual areas. This failure could reflect limitations in the data (e.g., a noise ceiling), or could reflect limitations of the DCNN as a model of computation in the brain. Understanding the source and structure of the unexplained variance could therefore provide helpful clues for improving models of brain computation. Here, we characterize the structure of the variance that DCNN-based encoding models cannot explain. Using a publicly available dataset of BOLD responses to natural scenes, we determined if the source of unexplained variance was shared across voxels, individual brains, retinotopic locations, and hierarchically distant visual brain areas. We answered these questions using voxel-to-voxel (vox2vox) models that predict activity in a target voxel given activity in a population of source voxels. We found that simple linear vox2vox models increased within-subject prediction accuracy over DCNN-based models for any pair of source/target visual areas, clearly demonstrating that the source of unexplained variance is widely shared within and across visual brain areas. However, vox2vox models were not more accurate than DCNN-based models when source and target voxels came from separate brains, demonstrating that the source of unexplained variance was not shared across brains. Furthermore, the weights of these vox2vox models permitted explicit readout of the receptive field location of target voxels, demonstrating that the source of unexplained variance induces correlations primarily between the activities of voxels with overlapping receptive fields. Finally, we found that vox2vox model prediction accuracy was heavily dependent upon the signed hierarchical distance between the source and target voxels: for feed-forward models (source area lower in the visual hierarchy than target area) prediction accuracy decreased with hierarchical distance between source and target. It did not decrease for feedback models. In contrast, the same analysis applied across layers of a DCNN did not reveal this feed-forward/feedback asymmetry. Given these results, we argue that the structured variance unexplained by DCNN-based encoding models is unlikely to be entirely caused by spatially correlated noise or eye movements; rather, our results point to a need for brain models that include endogenous dynamics and a pattern of connectivity that is not strictly feed-forward.