bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acetate supplementation rescues social deficits and alters transcriptional regulation in prefrontal cortex of Shank3 deficient mice
Authors: Osman Aya , Mervosh Nicholas L. , Strat Ana N. , Euston Tanner J. , Zipursky Gillian , Pollak Rebecca M. , Meckel Katherine R. , Tyler Scott R. , Chan Kenny L. , Grice Ariela Buxbaum , Drapeau Elodie , Litichevskiy Lev , Gill Jasleen , Thaiss Christoph A. , Buxbaum Joseph. D. , Breen Michael S. , Kiraly Drew D. 
Published: May 2020

AbstractAutism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder with complex pathophysiology including both genetic and environmental factors. Recent evidence demonstrates the gut microbiome and its resultant metabolome can influence brain and behavior and have been implicated in ASD. To investigate gene by microbiome interactions in a model for genetic risk of ASD, we utilize mutant mice carrying a deletion of the ASD-associatedShank3gene (Shank3KO).Shank3KOhave altered microbiome composition and function at baseline in addition to social deficits. Further depletion of the microbiome with antibiotics exacerbates social deficits inShank3KO, and results in transcriptional changes in the frontal cortex. Supplementation with the microbial metabolite acetate leads to reversal of social behavioral phenotypes even in mice with a depleted microbiome, and significantly alters transcriptional regulation in the prefrontal cortex. These results suggest a key role for the gut microbiome and the neuroactive metabolite acetate in regulating ASD-like behaviors.
1q21.3 amplification modulates therapy sensitivity in Triple Negative Breast Cancer
Authors: Chirravuri-Venkata Ramakanth , Ghersi Dario , Ganti Apar K. , Lakshmanan Imayavaramban , Chaudary Sanjib , Batra Surinder K. , Nasser Mohd Wasim 
Published: May 2020

AbstractThe contrast in therapy sensitivity and response across triple negative breast cancer (TNBC) patients suggest underlying genotypic heterogeneity. Using publicly available data, we found significant associations between DNA-level copy number alterations of 1q21.3 locus and therapy sensitivity. We show that in spite of their aggressive nature, 1q21.3 amplified tumors are more responsive to commonly used cytotoxic therapies, highlighting the relevance of 1q21.3 copy number status as a genetic marker for risk stratification, therapy selection and response.
Optimal time frequency analysis for biological data - pyBOAT
Authors: Mönke Gregor , Sorgenfrei Frieda A. , Schmal Christoph , Granada Adrián E. 
Published: May 2020

AbstractMethods for the quantification of rhythmic biological signals have been essential for the discovery of function and design of biological oscillators. Advances in live measurements have allowed recordings of unprecedented resolution revealing a new world of complex heterogeneous oscillations with multiple noisy non-stationary features. However, our understanding of the underlying mechanisms regulating these oscillations has been lagging behind, partially due to the lack of simple tools to reliably quantify these complex non-stationary features. With this challenge in mind, we have developed pyBOAT, a Python-based fully automatic stand-alone software that integrates multiple steps of non-stationary oscillatory time series analysis into an easy-to-use graphical user interface. pyBOAT implements continuous wavelet analysis which is specifically designed to reveal time-dependent features. In this work we illustrate the advantages of our tool by analyzing complex non-stationary time-series profiles. Our approach integrates data-visualization, optimized sinc-filter detrending, amplitude envelope removal and a subsequent continuous-wavelet based time-frequency analysis. Finally, using analytical considerations and numerical simulations we discuss unexpected pitfalls in commonly used smoothing and detrending operations.
A Behavioral Association Between Prediction Errors and Risk-Seeking: Theory and Evidence
Authors: Moeller Moritz , Grohn Jan , Manohar Sanjay , Bogacz Rafal 
Published: May 2020

AbstractReward prediction errors (RPEs) and risk preferences have two things in common: both can shape decision making behavior, and both are commonly associated with dopamine. RPEs drive value learning and are thought to be represented in the phasic release of striatal dopamine. Risk preferences bias choices towards or away from uncertainty; they can be manipulated with drugs that target the dopaminergic system. The common neural substrate suggests that RPEs and risk preferences might be linked on the level of behavior as well, but this has never been tested. Here, we aim to close this gap. First, we apply a recent theory of learning in the basal ganglia to predict how exactly RPEs might influence risk preferences. We then test our behavioral predictions using a novel bandit task in which value and risk vary independently across options. Critically, conditions are included where options vary in risk but are matched for value. We find that subjects become more risk seeking if choices are preceded by positive RPEs, and more risk averse if choices are preceded by negative RPEs. These findings cannot be explained by other known effects, such as nonlinear utility curves or dynamic learning rates. Finally, we show that RPE-induced risk-seeking is indexed by pupil dilation: participants with stronger pupillary correlates of RPE also show more pronounced behavioral effects.Author’s summaryMany of our decisions are based on expectations. Sometimes, however, surprises happen: outcomes are not as expected. Such discrepancies between expectations and actual outcomes are called prediction errors. Our brain recognises and uses such prediction errors to modify our expectations and make them more realistic--a process known as reinforcement learning. In particular, neurons that release the neurotransmitter dopamine show activity patterns that strongly resemble prediction errors. Interestingly, the same neurotransmitter is also known to regulate risk preferences: dopamine levels control our willingness to take risks. We theorised that, since learning signals cause dopamine release, they might change risk preferences as well. In this study, we test this hypothesis. We find that participants are more likely to make a risky choice just after they experienced an outcome that was better than expected, which is precisely what out theory predicts. This suggests that dopamine signalling can be ambiguous--a learning signal can be mistaken for an impulse to take a risk.
Histone deacetylase inhibitors butyrate and bufexamac inhibitde novoHIV-1 infection in CD4 T-cells
Authors: Chen Lin , Zutz Ariane , Phillippou-Massier Julia , Liebner Tim , Keppler Oliver T. , Choudhary Chunaram , Blum Helmut , Schölz Christian 
Published: May 2020

AbstractWhile current combined antiretroviral therapy (cART) allows control of HIV replication in patients and effectively suppresses plasma viral loads, it is unable to target latent reservoirs, which are responsible for virus rebound after discontinuation of therapy. Several histone deacetylase inhibitors (HDACIs) have been shown to target reservoirs and to reactivate latent HIV. While this effect is highly desired, it carries the risk that HIV-1 may be reactivated in tissue compartments were cART concentrations are insufficient and thus leading tode novoinfections in this sites. To address this concern, we evaluated the effect of different HDACIs for their ability to reverse HIV latency and to modulatede novoinfections. Two of the inhibitors, sodium butyrate and bufexamac, significantly inhibitedde novoHIV-1 infection in activated CD4+T-cells. Transcriptome and proteome analysis indicated global changes of protein abundancies, exhibited reduced proliferation of CD4+T-cells, and revealed butyrate-based proteasomal degradation of EP300, an important factor for HIV-1 replication. Our results disclose new potential treatment strategies and minimizes the concern of potential reservoir reseeding by HDACIs.
Fluorescence Lifetimes and Spectra of RPE and sub-RPE Deposits in Histology of Normal and AMD Eyes
Authors: Schultz Rowena , Gamage Kushmali C. L. K. , Messinger Jeffrey D. , Curcio Christine A. , Hammer Martin 
Published: May 2020

AbstractPurposeTo investigate autofluorescence lifetimes as well as spectral characteristics of drusen and retinal pigment epithelium (RPE) in age-related macular degeneration (AMD).MethodFluorescence lifetimes and spectra of five eyes with AMD and nine control eyes were analyzed in cryosections by means of two-photon excited fluorescence at 960 nm. Spectra were detected at 490 – 647nm. Lifetime was measured using time-correlated single photon counting in two spectral channels: 500-550nm and 550-700nm. The fluorescence decays over time were approximated by a series of three exponential functions and the amplitude-weighted mean fluorescence lifetime τmwas determined.Results196 sub-RPE deposits were identified (AMD n=76, healthy n=120) and 230 RPE sites recorded. The peak emission wavelength of drusen was significantly green-shifted compared to RPE (peak at 570nm vs. 610nm), but not different between patients and controls. Drusen showed considerably longer τmthan RPE: (ch1: 581 ± 163 ps vs. 177 ± 25 ps, ch2: 541 ± 125 ps vs. 285 ± 31 ps, p < 0.001). Drusen found in AMD eyes had longer lifetimes than drusen of controls (ch1: 650 ± 167 ps vs. 537 ± 145 ps, ch2: 600 ± 125 ps vs. 504 ± 111 ps, p < 0.001). In addition, drusen in AMD eyes showed a more homogenous fluorescence distribution and more drusen were larger than 63µm than in control eyes.ConclusionsEx vivo fluorescence imaging of drusen in cross-sections enables the separation of their autofluorescence from that of over- or underlying structures. Our analysis showed considerable variability of drusen lifetimes but not spectra. This indicates that drusen consist of a variety of different fluorophores or expose the same fluorophores to different microenvironments. Changes in drusen lifetimes could be related to AMD progression.
Comparative analysis of genome-wide DNA methylation identifies patterns that associate with conserved transcriptional programs in osteosarcoma
Authors: Mills Lauren J. , Scott Milcah C. , Shah Pankti , Cunanan Anne R. , Deshpande Archana , Auch Benjamin , Curtin Bridget , Beckman Kenneth B. , Spector Logan G. , Sarver Aaron L. , Subramanian Subbaya , Richmond Todd A. , Modiano Jaime F. 
Published: May 2020

AbstractOsteosarcoma is an aggressive tumor of the bone that primarily affects young adults and adolescents. Osteosarcoma is characterized by genomic chaos and heterogeneity. While inactivation of tumor suppressor p53TP53is nearly universal other high frequency mutations or structural variations have not been identified. Despite this genomic heterogeneity, key conserved transcriptional programs associated with survival have been identified across human, canine and induced murine osteosarcoma. The epigenomic landscape, including DNA methylation, plays a key role in establishing transcriptional programs in all cell types. The role of epigenetic dysregulation has been studied in a variety of cancers but has yet to be explored at scale in osteosarcoma. Here we examined genome-wide DNA methylation patterns in 24 human and 44 canine osteosarcoma samples identifying groups of highly correlated DNA methylation marks in human and canine osteosarcoma samples. We also link specific DNA methylation patterns to key transcriptional programs in both human and canine osteosarcoma. Building on previous work, we built a DNA methylation-based measure for the presence and abundance of various immune cell types in osteosarcoma. Finally, we determined that the underlying state of the tumor, and not changes in cell composition, were the main driver of differences in DNA methylation across the human and canine samples.SignificanceThis is the first large scale study of DNA methylation in osteosarcoma and lays the ground work for the exploration of DNA methylation programs that help establish conserved transcriptional programs in the context of different genomic landscapes.
An Axon-Pathfinding Mechanism Preserves Epithelial Tissue Integrity
Authors: Cammarota Christian M. , Finegan Tara M. , Wilson Tyler J. , Yang Sifan , Bergstralh Dan T. 
Published: May 2020

SummaryDividing cells often move apically within epithelial tissue layers, likely to escape the spatial confinement of their neighbors. Because of this movement, daughter cells may be born displaced from the tissue layer. Reintegration of these displaced cells helps support tissue growth and maintain tissue architecture. In theDrosophilafollicular epithelium, reintegration relies on the immunoglobulin-superfamily cell-adhesion molecules (IgCAMs) Neuroglian and Fasciclin 2, which line cell-cell borders1. These molecules have been described in epithelia, but are well-studied for their roles in neural development2–8. We show here that reintegration works in the same way as IgCAM-mediated axon growth and pathfinding; it relies not only on extracellular adhesion but also mechanical coupling between IgCAMs and the lateral Spectrin-Based Membrane Skeleton. Our work indicates that reintegration is mediated by a distinct epithelial cell-cell junction that is compositionally and functionally equivalent to junctions made between axons.
Tumor -Associated MUC1 Regulates TGF-β Signaling and Function in Pancreatic Ductal Adenocarcinoma
Authors: Grover Priyanka , Nath Sritama , Bose Mukulika , Sanders Alexa J. , Brouwer Cory , Nitika  , Zhou Ru , Yazdanifar Mahboubeh , Ahmad Mohammad , Wu Shu-ta , Truman Andrew W. , Mukherjee Pinku 
Published: May 2020

AbstractPancreatic ductal adenocarcinoma (PDA) is one of the most lethal human cancers. Transforming Growth Factor Beta (TGF-β) is a cytokine that switches from a tumor-suppressor to a tumor promoter throughout tumor development, by a yet unknown mechanism. Tumor associated MUC1 (tMUC1) is aberrantly glycosylated and overexpressed in >80% of PDAs and is associated with poor prognosis. The cytoplasmic tail of MUC1 (MUC1-CT) interacts with other oncogenic proteins promoting tumor progression and metastasis. We hypothesize that tMUC1 levels regulate TGF-β functions in PDAin vitroandin vivo. We report that high-tMUC1 expression positively correlates to TGF-βRII and negatively to TGF-βRI receptors. In response to TGF-β1, high tMUC1 expressing PDA cells undergo c-Src phosphorylation, and activation of the Erk/MAPK pathway; while low tMUC1 expressing cells activate the Smad2/3 pathway, enhancing cell death. Correspondingly, mice bearing tMUC1-high tumors responded to TGF-β1 neutralizing antibodyin vivoshowing significantly retarded tumor growth. Analysis of clinical data from TCGA revealed significant alterations in gene-gene correlations in the TGF-β pathway in tMUC1 high versus tMUC1 low samples. This study deepens our understanding of tMUC1-regulated TGF-β’s paradoxical function in PDA and establishes tMUC1 as a potential biomarker to predict response to TGF-β-targeted therapies.
UV damage induces G3BP1-dependent stress granule formation that is not driven by translation arrest via mTOR inhibition
Authors: Ying Shan , Khaperskyy Denys A. 
Published: May 2020

ABSTRACTTranslation arrest is a part of the cellular stress response that decreases energy consumption and enables rapid reprioritisation of gene expression. Often translation arrest leads to condensation of untranslated messenger ribonucleoproteins (mRNPs) into stress granules (SGs). Studies into mechanisms of SG formation and functions are complicated because various types of stress cause formation of SGs with different properties and composition. In this work we focused on the mechanism of SG formation triggered by UV damage. We demonstrate that UV-induced inhibition of translation does not cause dissociation of the 48S preinitiation complexes. The catalytic activity of the general control non-derepressible 2 (GCN2) kinase contributes to UV-induced SG formation, which is independent of the GCN2-mediated phosphorylation of the eukaryotic translation initiation factor 2α. Like many other types of SGs, condensation of UV-induced granules specifically requires the Ras-GTPase-Activating Protein SH3-Domain-Binding Protein 1 (G3BP1). Our work reveals that in UV-treated cells the mechanisms of translation arrest and SG formation may be unlinked, resulting in condensation of ribonucleoproteins that do not represent the major type of polysome-free preinitiation complexes that accumulate in the cytoplasm.
Concurrent stem- and lineage-affiliated chromatin programs precede hematopoietic lineage restriction
Authors: Safi Fatemeh , Dhapola Parashar , Warsi Sarah , Erlandsson Eva , Sitnicka Ewa , Bryder David , Böiers Charlotta , Thakur Ram Krishna , Karlsson Göran 
Published: May 2020

SUMMARYThe emerging notion of hematopoietic stem- and progenitor cells (HSPCs) as a low-primed cloud without sharply demarcated gene expression programs raises the question on how cellular fate options emerge, and at which stem-like stage lineage priming is initiated. Here we investigated single-cell chromatin accessibility of Lineage−, cKit+, Sca1+(LSK) HSPCs spanning the early differentiation landscape. Application of a signal-processing algorithm to detect transition points corresponding to massive alterations in accessibility of 571 transcription factor-motifs revealed a population of LSK FMS-like tyrosine kinase 3(Flt3)intCD9highcells that concurrently display stem-like and lineage-affiliated chromatin signatures pointing to a simultaneous gain of both Lympho-Myeloid and Megakaryocyte-Erythroid programs. Molecularly and functionally, these cells position between stem cells and committed progenitors, display multi-lineage capacity in vitro and in vivo, but lack self-renewal activity. This integrative molecular analysis resolves the heterogeneity of cells along hematopoietic differentiation and permits investigation of chromatin-mediated transition between multipotency and lineage restriction.
TwoCaenorhabditis eleganscalponin-related proteins have overlapping functions to maintain cytoskeletal integrity and are essential for reproduction
Authors: Ono Shoichiro , Ono Kanako 
Published: May 2020

AbstractMulticellular organisms have multiple genes encoding calponins and calponin-related proteins, and some of these are known to regulate actin cytoskeletal dynamics and contractility. However, functional similarities and differences among these proteins are largely unknown. In the nematodeCaenorhabditis elegans, UNC-87 is a calponin-related protein with seven calponin-like (CLIK) motifs and is required for maintenance of contractile apparatuses in muscle cells. Here, we report that CLIK-1, another calponin-related protein that also contains seven CLIK motifs, has an overlapping function with UNC-87 to maintain actin cytoskeletal integrityin vivoand has both common and different actin-regulatory activitiesin vitro. CLIK-1 is predominantly expressed in the body wall muscle and somatic gonad, where UNC-87 is also expressed.unc-87mutation causes cytoskeletal defects in the body wall muscle and somatic gonad, whereasclik-1depletion alone causes no detectable phenotypes. However, simultaneous depletion ofclik-1andunc-87caused sterility due to ovulation failure by severely affecting the contractile actin networks in the myoepithelial sheath of the somatic gonad.In vitro, UNC-87 bundles actin filaments. However, CLIK-1 binds to actin filaments without bundling them and is antagonistic to UNC-87 in filament bundling. UNC-87 and CLIK-1 share common functions to inhibit cofilin binding and allow tropomyosin binding to actin filaments, suggesting that both proteins stabilize actin filaments. Thus, partially redundant functions of UNC-87 and CLIK-1 in ovulation is likely mediated by their common actin-regulatory activities, but their distinct activities in actin bundling suggest that they also have different biological functions.
Making ends meet: new functions of mRNA secondary structure
Authors: Ermolenko Dmitri N. , Mathews David 
Published: May 2020

AbstractThe 5’ cap and 3’ poly(A) tail of mRNA are known to synergistically regulate mRNA translation and stability. Recent computational and experimental studies revealed that both protein-coding and non-coding RNAs will fold with extensive intramolecular secondary structure, which will result in close distances between the sequence ends. This proximity of the ends is a sequence-independent, universal property of most RNAs. Only low-complexity sequences without guanosines are without secondary structure and exhibit end-to-end distances expected for RNA random coils. The innate proximity of RNA ends might have important biological implications that remain unexplored. In particular, the inherent compactness of mRNA might regulate translation initiation by facilitating the formation of protein complexes that bridge mRNA 5’ and 3’ ends. Additionally, the proximity of mRNA ends might mediate coupling of 3′ deadenylation to 5′ end mRNA decay.
Enterohepatic Transcription Factor CREB3L3 Protects Atherosclerosis via SREBP Competitive Inhibition
Authors: Nakagawa Yoshimi , Wang Yunong , Han Song-iee , Okuda Kanako , Oishi Asayo , Yagishita Yuka , Kumagai Kae , Ohno Hiroshi , Osaki Yoshinori , Mizunoe Yuhei , Araki Masaya , Murayama Yuki , Iwasaki Hitoshi , Konishi Morichika , Itoh Nobuyuki , Matsuzaka Takashi , Sone Hirohito , Yamada Nobuhiro , Shimano Hitoshi 
Published: May 2020

SummaryCREB3L3 is a membrane-bound transcription factor to maintain lipid metabolism in the liver and small intestine. CREB3L3 ablation inLdlr-/-mice exacerbated hyperlipidemia with remnant ApoB-containing lipoprotein accumulation, developing enhanced aortic atheroma formation, whose extent was additive between liver- and intestine-specific deletion. Conversely, hepatic nuclear CREB3L3 overexpression markedly suppressed atherosclerosis with amelioration of hyperlipidemia. CREB3L3 directly upregulates anti-atherogenic FGF21 and ApoA4, whereas antagonizes hepatic SREBP-mediated lipogenic and cholesterogenic genes and regulates LXR-regulated genes involved in intestinal transport of cholesterol. CREB3L3 deficiency accumulates nuclear SREBP proteins. Because both transcriptional factors share the cleavage system for nuclear transactivation, full-length CREB3L3 and SREBPs on endoplasmic reticulum (ER) functionally inhibit each other. CREB3L3 competitively antagonizes SREBPs for ER-Golgi transport, resulting in ER retention and proteolytic activation inhibition at Golgi, and vice versa. Collectively, due to this new mechanistic interaction between CREB3L3 and SREBPs under atherogenic conditions, CREB3L3 has multi-potent protective effects against atherosclerosis.