bluuebunny/crossref_metadata_2025_split huggingface dataset:
Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma
Authors: Miklja Zachary , Yadav Viveka Nand , Cartaxo Rodrigo T. , Siada Ruby , Thomas Chase C. , Cummings Jessica R. , Mullan Brendan , Stallard Stefanie , Paul Alyssa , Bruzek Amy K. , Wierzbicki Kyle , Yang Tao , Garcia Taylor , Wolfe Ian , Leonard Marcia , Robertson Patricia L. , Garton Hugh J.L. , Wahl Daniel R. , Parmar Hemant , Sarkaria Jann N. , Kline Cassie , Mueller Sabine , Nicolaides Theodore , Glasser Chana , Leary Sarah E.S. , Venneti Sriram , Kumar-Sinha Chandan , Chinnaiyan Arul M. , Mody Rajen , Pai Manjunath P. , Phoenix Timothy N. , Marini Bernard L. , Koschmann Carl 
Published: January 2020

AbstractBackgroundPediatric and adult high-grade glioma (HGG) frequently harbor PDGFRA alterations. We hypothesized that co-treatment with everolimus may improve the efficacy of dasatinib in PDGFRα-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib.MethodsDose response, synergism studies, P-gp inhibition and pharmacokinetic studies were performed on in vitro and in vivo human and mouse models of HGG. Six patients with recurrent PDGFRα-driven glioma were treated with dasatinib and everolimus.ResultsDasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a variety of PDGFRA alterations. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents, with reduction in mTOR signaling that persists after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended survival of PPK tumor bearing mice. Pediatric patients (n=6) with glioma tolerated this combination without significant adverse events. Recurrent patients (n=4) demonstrated median overall survival of 8.5 months.ConclusionEfficacy of dasatinib treatment of PDGFRα-driven HGG is improved with everolimus and suggests a promising route for improving targeted therapy for this patient population.Trial RegistrationClinicalTrials.gov NCT03352427FundingThe authors thank the patients and their families for participation in this study. CK is supported by NIH/NINDS K08-NS099427-01, the University of Michigan Chad Carr Pediatric Brain Tumor Center, the Chad Tough Foundation, Hyundai Hope on Wheels, Catching up With Jack, Prayers from Maria Foundation, U CAN-CER VIVE FOUNDATION, Morgan Behen Golf Classic, and the DIPG Collaborative. The PEDS-MIONCOSEQ study was supported by grant 1UM1HG006508 from the National Institutes of Health Clinical Sequencing Exploratory Research Award (PI: Arul Chinnaiyan).
The use of wearable technology to objectively measure sleep quality and physical activity among pregnant women in urban Lima, Peru: A pilot feasibility study
Authors: Galea Jerome T. , Ramos Karen , Coit Julia , Friedman Lauren E. , Contreras Carmen , Dueñas Milagros , Hernandez Giuliana Noris , Muster Caroline , Lecca Leonid , Gelaye Bizu 
Published: January 2020

AbstractSleep quality and physical activity can affect the mental and physical health of pregnant women and their unborn babies. We investigated the feasibility of assessing sleep quality and physical activity among pregnant women in Peru. Twenty women maintained sleep logs and wore ActiSleep devices for seven consecutive days; 13 had sufficient data for analysis. Mean sleep duration was 6.9 hours (SD = 1.4). Sleep efficiency was 77.9%. Participants averaged of 6,029 steps per day (SD = 3,087). Objective assessment of sleep quality and physical activity was feasible. Wearable technology has applications in healthcare to improve sleep quality and physical activity.
Human Tau Isoform Aggregation and Selective Detection of Misfolded Tau from Post-Mortem Alzheimer’s Disease Brains
Authors: Wu Ling , Wang Zerui , Ladd Shradha , Dougharty Darren T. , Madhavan Sidharth S. , Marcus Madeleine , Henderson Frances , Ray W. Keith , Tan Christopher , Siedlak Sandra , Li Jianyong , Helm Richard F. , Zhu Xiongwei , Bloom George S. , Zou Wen-Quan , Xu Bin 
Published: January 2020

AbstractTau aggregates are present in a large number of neurodegenerative diseases known as “tauopathies”, including Alzheimer’s disease (AD). As there are six human tau isoforms in brain tissues and both 3R and 4R isoforms have been observed in the neuronal inclusions, we tested whether tau isoforms behave differently in aggregation. We discovered that all six tau isoforms are capable of forming PHF-tau like filaments and the 3R tau isoforms aggregate significantly faster than their 4R counterparts. We further mapped key segments of tau isoforms that contribute to their aggregation kinetics, where it was determined that microtubule binding domains R2 and R3 were the major contributors to tau aggregation. To evaluate the feasibility of using the six recombinant tau isoforms as substrates to amplify misfolded tau, we demonstrated that full-length human tau isoforms can seed and detect misfolded tau from the post-mortem AD brain tissues with high specificity by an ultrasensitive technology termed real-time quaking-induced conversion (RT-QuIC). Mass spectrometric analysis of PHF-tau samples extracted from AD brains identified peptides corresponding to all major forms of human brain tau isoforms along with a consensus hyperphosphorylated peptide near the C-terminus. Together, our findings not only reveal new aggregation kinetic properties of human tau isoforms, support the development of methods to quantitatively measure misfolded human tau isoforms in AD brains, but also uncover the capability of full-length human tau isoforms as substrates for “prion-like” tau seeding by RT-QuIC assays that may be used for new biomarker development for AD and other tauopathy diagnosis.
Weekend light shifts evoke persistentDrosophilacircadian neural network desynchrony
Authors: Nave Ceazar , Roberts Logan , Hwu Patrick , Estrella Jerson D. , Vo Thanh C , Nguyen Thanh H , Pervolarakis Nicholas , Shaw Paul J. , Leise Tanya L. , Holmes Todd C. 
Published: January 2020

AbstractBillions of people subject themselves to phase-shifting light signals on a weekly basis by remaining active later at night and sleeping in later on weekends relative to weekday for up to a 3hr weekend light shift (WLS). Unnatural light signals disrupt circadian rhythms and physiology and behavior. Real-time light responses of mammalian suprachiasmatic nucleus are unmeasurable at single cell resolution. We comparedDrosophilawhole-circadian circuit responses between unshifted daytime/nighttime schedule and a 3hr WLS schedule at the single-cell resolution in cultured adultDrosophilabrains using real-time bioluminescence imaging of the PERIOD protein for 11 days to determine how light shifts alter biological clock entrainment and stability. We find that circadian circuits show highly synchronous oscillations across all major circadian neuronal subgroups in unshifted light schedules. In contrast, circadian circuits exposed to a WLS schedule show significantly dampened oscillator synchrony and rhythmicity in most circadian neurons during, and after exposure. The WLS schedule first desynchronizes lateral ventral neuron (LNv) oscillations and the LNv are the last to resynchronize upon returning to a simulated weekday schedule. Surprisingly, one circadian subgroup, the dorsal neuron group-3 (DN3s), robustly increase their within-group synchrony in response to WLS exposure. Intact adult flies exposed to the WLS schedule show post-WLS transient defects in sleep stability, learning, and memory. Our findings suggest that WLS schedules disrupt circuit-wide circadian neuronal oscillator synchrony for much of the week, thus leading to observed behavioral defects in sleep, learning, and memory.Significance StatementThe circadian clock controls numerous aspects of daily animal physiology, metabolism and behavior. Shift work in humans is harmful. Our understanding of circadian circuit-level oscillations stem fromex vivoimaging of mammalian suprachiasmatic nucleus (SCN) brain slices. However, our knowledge is limited to investigations without direct interrogation of phase-shifting light signals. We measured circuit-level circadian responses to a WLS protocol in light sensitiveex vivo Drosophilawhole-brain preparation and find robust sub-circuit-specific oscillator desynchrony/resynchrony responses to light. These circuit-level behaviors correspond to our observed functional defects in learning and memory, and sleep pattern disruptionin vivo. Our results reflect that WLS cause circadian-circuit desynchronization and correlate with disrupted cognitive and sleep performance.
The predictive power of the microbiome exceeds that of genome-wide association studies in the discrimination of complex human disease
Authors: Tierney Braden T , He Yixuan , Church George M , Segal Eran , Kostic Aleksandar D , Patel Chirag J 
Published: January 2020

AbstractOver the past decade, studies of the human genome and microbiome have deepened our understanding of the connections between human genes, environments, microbes, and disease. For example, the sheer number of indicators of the microbiome and human genetic common variants associated with disease has been immense, but clinical utility has been elusive. Here, we compared the predictive capabilities of the human microbiome versus human genomic common variants across 13 common diseases. We concluded that microbiomic indicators outperform human genetics in predicting host phenotype (overall Microbiome-Association-Study [MAS] area under the curve [AUC] = 0.79 [SE = 0.03], overall Genome-Wide-Association-Study [GWAS] AUC = 0.67 [SE = 0.02]). Our results, while preliminary and focused on a subset of the totality of disease, demonstrate the relative predictive ability of the microbiome, indicating that it may outperform human genetics in discriminating human disease cases and controls. They additionally motivate the need for population-level microbiome sequencing resources, akin to the UK Biobank, to further improve and reproduce metagenomic models of disease.
Dual roles of the Sterol Recognition Region in Hedgehog protein modification
Authors: Purohit Rahul , Peng Daniel S. , Vielmas Erika , Ondrus Alison E. 
Published: January 2020

AbstractNature provides a number of mechanisms to encode dynamic information in biomolecules. In metazoans, there exist rare chemical modifications that occur through entirely unique mechanistic regimes. One such example occurs in the Hedgehog (Hh) morphogens, proteins singular across all domains of life for the nature of their covalent ligation to cholesterol. The isoform- and context-specific efficiency of the ligation reaction has profound impact on the activity of Hh morphogens and represents an unexplored aspect of Hh ligand-dependent cancers. To elucidate the chemical mechanism of this modification, we have defined roles of the uncharacterized sterol recognition region (SRR) in Hh proteins. We use a combination of sequence conservation, directed mutagenesis, and biochemical assays to specify residues of the SRR that are responsible for cellular and biochemical processes in Hh cholesterolysis. Our investigations offer the first functional template of this region, providing opportunities to identify parallel reactivity in nature and revealing new mechanisms that can be exploited as tools in chemical biology.
Molecular height measurement by cell surface optical profilometry (CSOP)
Authors: Son Sungmin , Takatori Sho C. , Belardi Brian , Podolski Marija , Bakalar Matthew H. , Fletcher Daniel A. 
Published: January 2020

AbstractThe physical dimensions of proteins and glycans on cell surfaces can critically affect cell function, for example by preventing close contact between cells and limiting receptor accessibility. However, high-resolution measurements of molecular heights on native cell membranes have been difficult to obtain. Here we present a simple and rapid method that achieves nanometer height resolution by localizing fluorophores at the tip and base of cell surface molecules and determining their separation by radially averaging across many molecules. We use this method, which we call cell surface optical profilometry (CSOP), to quantify height of key multi-domain proteins on a model macrophage and cancer cell, as well as to capture average protein and glycan heights on native cell membranes. We show that average height of a protein is significantly smaller than its contour length due to thermally driven bending and rotation on the membrane and that height strongly depends on local surface and solution conditions. We find that average height increases with cell surface molecular crowding, while it decreases with solution crowding by solutes, both of which we confirm with molecular dynamics simulations. We also use experiments and simulations to determine the height of an epitope based on the location of an antibody, which allows CSOP to profile various proteins and glycans on a native cell surface using antibodies and lectins. This versatile method for profiling cell surfaces has the potential to advance understanding of the molecular landscape of cells and its role in cell function.
Correlated Gene Modules Uncovered by Single-Cell Transcriptomics with High Detectability and Accuracy
Authors: Chapman Alec R. , Lee David F. , Cai Wenting , Ma Wenping , Li Xiang , Sun Wenjie , Xie X. Sunney 
Published: January 2020

AbstractSingle cell transcriptome sequencing has become extremely useful for cell typing. However, such differential expression data has shed little light on regulatory relationships among genes. Here, by examining pairwise correlations between mRNA levels of any two genes under steady-state conditions, we uncovered correlated gene modules (CGMs), clusters of intercorrelated genes that carry out certain biological functions together. We report a novel single-cell RNA-seq method called MALBAC-DT with higher detectability and accuracy, allowing determination of the covariance matrix of the expressed mRNAs for a homogenous cell population. We observed a prevalence of positive correlations between pairs of genes, with higher correlations corresponding to higher likelihoods of protein-protein interactions. Some CGMs, such as the p53 module in a cancer cell line, are cell type specific, while others, such as the protein synthesis CGM, are shared by different cell types. CGMs distinguished direct targets of p53 and exposed different modes of regulation of these genes in different cell types. Our covariance analyses of steady-state fluctuations provides a powerful way to advance our functional understanding of gene-to-gene interactions.
Improving protein alignment algorithms using amino-acid hydrophobicities - Applications of TMATCH, A new algorithms
Authors: Cavanaugh David P. , Chittur Krishnan K. 
Published: January 2020

ABSTRACTMotivationSequence database search and matching algorithms are an important tool when trying to understand the structure (and so the function) of proteins. Proteins with similar structure and function often have very similar primary structure. There are however many cases where proteins with similar structure have very different primary structures. Substitution matrices (PAM, BLOSUM, Gonnett) can be used to identify proteins of similar structure, but they fail when the sequence similarity falls below about 25%.ResultsWe have described a new algorithm for examining the the primary structure of proteins against a database of known proteins with a new hydrophobicity index. In this paper, we examine the ability of TMATCH to identify proteins of similar structure using sequence matching with the hydrophobicity index. We compare results from TMATCH with those obtained using FASTA and PSI-BLAST. We show that by using similarity patterns spread across the entire length of two proteins we get a more robust indicator of remote relatedness than relying upon high similarity scoring pair regions.AvailabilityThe program TMATCH is available on requestContactchitturk@uah.edu
ATR expands embryonic stem cell fate potential in response to replication stress
Authors: Atashpaz Sina , Shams Sara Samadi , Gonzalez Javier Martin , Sebestyén Endre , Arghavanifard Negar , Gnocchi Andrea , Albers Eliene , Minardi Simone , Faga Giovanni , Soffientini Paolo , Allievi Elisa , Cancila Valeria , Bachi Angela , Fernandez-Capetillo Oscar , Tripodo Claudio , Ferrari Francesco , López-Contreras Andrés Joaquin , Costanzo Vincenzo 
Published: January 2020

SummaryUnrepaired DNA damage during embryonic development can be potentially inherited by a large population of cells. However, the quality control mechanisms that minimize the contribution of damaged cells to developing embryos remain poorly understood.Here, we uncovered an ATR- and CHK1-mediated transcriptional response to replication stress (RS) in ESCs that induces genes expressed in totipotent two-cell (2C) stage embryos and 2C-like cells. This response is mediated byDux,a multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals. In response to RS, DUX triggers the transcription of 2C-like markers such as murine endogenous retrovirus-like elements (MERVL) andZscan4.This response can also be elicited by ETAA1-mediated ATR activation in the absence of RS. ATR-mediated activation of DUX requires GSRF1 dependent post-transcriptional regulation ofDuxmRNA. Strikingly, activation of ATR expands ESCs fate potential by extending their contribution to both embryonic and extra­embryonic tissues. These findings define a novel ATR dependent pathway involved in maintaining genome stability in developing embryos by controlling ESCs fate in response to RS.
Associative Learning and Motivation Differentially Requires Neuroligin-1 at Excitatory Synapses
Authors: Luo Jiaqi , Tan Jessica M , Nithianantharajah Jess 
Published: January 2020

ABSTRACTIn a changing environment, a challenge for the brain is to flexibly guide adaptive behavior towards survival. Understanding how these decision-making processes and underlying neural computations are orchestrated by the structural components of the brain, from circuits to cells, and ultimately the signaling complex of proteins at synapses, is central to elucidating the mechanisms that shape normal and abnormal brain connectivity, plasticity and behavior. At excitatory synapses, neuroligin-1 (Nlgn1) a postsynaptic cell-adhesion molecule required for the formation of trans-synaptic complexes with presynaptic partners is critical for regulating synapse specification, function and plasticity. Extensive evidence shows Nlgn1 is essential for synaptic transmission and long-term plasticity, but how these signaling processes ultimately regulate components of cognitive behavior is much less understood. Here, employing a comprehensive battery of touchscreen-based cognitive assays, we measured two key decision problems: i) the ability to learn and exploit the associative structure of the environment and ii) the trade-off between potential rewards and costs, or positive and negative utilities associated with available actions. We found that mice lacking Nlgn1 have an intact capacity to acquire complex associative structures and adjust learned associations. However, loss of Nlgn1 alters motivation leading to areducedwillingness to overcome response effort for reward and anincreasedwillingness to exert effort to escape an aversive situation. We suggest Nlgn1 may be important for balancing the weighting on positive and negative utilities in reward-cost trade-off. Our findings identify Nlgn1 is essential for regulating distinct cognitive processes underlying decision-making, providing evidence of a new model for dissociating the computations underlying learning and motivational processing.
BET bromodomain inhibitor HMBA synergizes with MEK inhibition in treatment of malignant glioma
Authors: Funck-Brentano Elisa , Vizlin-Hodzic Dzeneta , Nilsson Jonas A. , Nilsson Lisa M. 
Published: January 2020

Abstract(1)BackgroundBET bromodomain proteins regulate transcription by binding acetylated histones and attracting key factors for e.g. transcriptional elongation. BET inhibitors have been developed to block pathogenic processes such as cancer and inflammation. Despite having potent biological activities, BET inhibitors have still not made a breakthrough in clinical use for treating cancer. Multiple resistance mechanisms have been proposed but thus far no attempts to block this in glioma has been made.(2)MethodsHere, we have conducted a pharmacological synergy screen in glioma cells to search for possible combination treatments augmenting the apoptotic response to BET inhibitors. We first used HMBA, a compound that was developed as a differentiation therapy four decades ago but more recently was shown to primarily inhibit BET bromodomain proteins. Data was also generated using other BET inhibitors.(3)ResultsIn the synergy screen, we discovered that several MEK inhibitors can enhance apoptosis in response to HMBA in rat and human glioma cells in vitro as well as in vivo xenografts. The combination is not unique to HMBA but also other BET inhibitors such as JQ1 and I-BET-762 can synergize with MEK inhibitors.(4)ConclusionsOur findings validate a combination therapy previously demonstrated to exhibit anti-cancer activities in multiple other tumor types but which appears to have been lost in translation to the clinic.
Granular Transcriptomic Signatures Derived from Independent Component Analysis of Bulk Nervous Tissue for Studying Labile Brain Physiologies
Authors: Rusan Zeid M , Cary Michael P , Bainton Roland J 
Published: January 2020

AbstractMulticellular organisms employ concurrent gene regulatory programs to control development and physiology of cells and tissues. TheDrosophila melanogastermodel system has a remarkable history of revealing the genes and mechanisms underlying fundamental biology yet much remains unclear. In particular, brain xenobiotic protection and endobiotic regulatory systems that require transcriptional coordination across different cell types, operating in parallel with the primary nervous system and metabolic functions of each cell type, are still poorly understood. Here we use the unsupervised machine learning method independent component analysis (ICA) on majority fresh-frozen, bulk tissue microarrays to define biologically pertinent gene expression signatures which are sparse, i.e. each involving only a fraction of all fly genes. We optimize the gene expression signature definitions partly through repeated application of a stochastic ICA algorithm to a compendium of 3,346 microarrays from 221 experiments provided by theDrosophilaresearch community. Our optimized ICA model of pan fly gene expression consists of 850 modules of co-regulated genes that map to tissue developmental stages, disease states, cell-autonomous pathways and presumably novel processes. Importantly, we show biologically relevant gene modules expressed at varying amplitudes in whole brain and isolated adult blood-brain barrier cell levels. Thus, whole tissue derived ICA transcriptional signatures that transcend single cell type boundaries provide a window into the transcriptional states of difficult to isolate cell ensembles maintaining delicate brain physiologies. We believe the fly ICA gene expression signatures set, by virtue of the success of ICA at inferring robust often low amplitude patterns across large datasets and the quality of the input samples, to be an important asset for analyzing compendium and newly generated microarray or RNA-seq expression datasets.