bluuebunny/crossref_metadata_2025_split huggingface dataset:
Keep calm: the intestinal barrier at the interface of peace and war
Authors: Thoo Lester , Noti Mario , Krebs Philippe 
Published: November 2019

AbstractEpithelial barriers have to constantly cope with both harmless and harmful stimuli. The epithelial barrier therefore serves as a dynamic and not static wall to safeguard its proper physiological function while ensuring protection. This is achieved through multiple defence mechanisms involving various cell types - epithelial and non-epithelial - that work in an integrated manner to build protective barriers at mucosal sites. Damage may nevertheless occur, due to pathogens, physical insults or dysregulated immune responses, which trigger a physiologic acute or a pathologic chronic inflammatory cascade. Inflammation is often viewed as a pathological condition, particularly due to the increasing prevalence of chronic inflammatory (intestinal) diseases. However, inflammation is also necessary for wound healing. The aetiology of chronic inflammatory diseases is incompletely understood and identification of the underlying mechanisms would reveal additional therapeutic approaches. Resolution is an active host response to end ongoing inflammation but its relevance is under-appreciated. Currently, most therapies aim at dampening inflammation at damaged mucosal sites, yet these approaches do not efficiently shut down the inflammation process nor repair the epithelial barrier. Therefore, future treatment strategies should also promote the resolution phase. Yet, the task of repairing the barrier can be an arduous endeavour considering its multiple integrated layers of defence - which is advantageous for damage prevention but becomes challenging to repair at multiple levels. In this review, using the intestines as a model epithelial organ and barrier paradigm, we describe the consequences of chronic inflammation and highlight the importance of the mucosae to engage resolving processes to restore epithelial barrier integrity and function. We further discuss the contribution of pre-mRNA alternative splicing to barrier integrity and intestinal homeostasis. Following discussions on current open questions and challenges, we propose a model in which resolution of inflammation represents a key mechanism for the restoration of epithelial integrity and function.
Inhibition of UCHL1 by LDN-57444 attenuates Ang II–Induced atrial fibrillation in mice
Authors: Bi Hai-Lian , Zhang Yun-Long , Yang Jie , Shu Qing , Yang Xiao-Lei , Yan Xiao , Chen Chen , Li Zhi , Li Hui-Hua 
Published: November 2019

AbstractAtrial fibrillation (AF) is the most common human arrhythmia in clinical practice and may be promoted by atrial inflammation and fibrosis. Ubiquitination is an important posttranslational modification process that is reversed by deubiquitinating enzymes (DUBs). DUBs play critical roles in modulating the degradation, activity, trafficking, and recycling of substrates. However, less research has focused on the role of DUBs in AF. Here, we investigated the effect of ubiquitin C-terminal hydrolase 1 (UCHL1), an important DUB, on the development of AF induced by angiotensin II (Ang II). Male wild-type mice were treated with the UCHL1 inhibitor LDN57444 (LDN) at a dose of 40 μg/kg and infused with Ang II (2000 ng/kg/min) for 3 weeks. Our results showed that Ang II-infused wild-type (WT) mice had higher systolic blood pressure and an increased incidence and duration of AF. Conversely, this effect was attenuated in LDN-treated mice. Moreover, the administration of LDN significantly reduced Ang II-induced left atrial dilation, fibrosis, inflammatory cell infiltration, and reactive oxygen species (ROS) production. Mechanistically, LDN treatment inhibited the activation of multiple signaling pathways (the AKT, ERK1/2, HIF-1α, and TGF-β/smad2/3 pathways) and the expression of CX43 protein in atrial tissues compared with that in vehicle-treated control mice. Overall, our study identified UCHL1 as a novel regulator that contributes to Ang II-induced AF and suggests that the administration of LDN may represent a potential therapeutic approach for treating hypertensive AF.
AZD7648 is a potent and selective DNA-PK inhibitor that enhances radiation, chemotherapy and olaparib activity
Authors: Fok Jacqueline H. L. , Ramos-Montoya Antonio , Vazquez-Chantada Mercedes , Wijnhoven Paul W. G. , Follia Valeria , James Neil , Farrington Paul M. , Karmokar Ankur , Willis Sophie E. , Cairns Jonathan , Nikkilä Jenni , Beattie David , Lamont Gillian M. , Finlay M. Raymond V. , Wilson Joanne , Smith Aaron , O’Connor Lenka Oplustil , Ling Stephanie , Fawell Stephen E. , O’Connor Mark J. , Hollingsworth Simon J. , Dean Emma , Goldberg Frederick W. , Davies Barry R. , Cadogan Elaine B. 
Published: November 2019

AbstractDNA-dependent protein kinase (DNA-PK) is a critical player in the DNA damage response (DDR) and instrumental in the non-homologous end-joining pathway (NHEJ) used to detect and repair DNA double-strand breaks (DSBs). We demonstrate that the potent and highly selective DNA-PK inhibitor, AZD7648, is an efficient sensitizer of radiation- and doxorubicin-induced DNA damage, with combinations in xenograft and patient-derived xenograft (PDX) models inducing sustained regressions. Using ATM-deficient cells, we demonstrate that AZD7648, in combination with the PARP inhibitor olaparib, increases genomic instability, resulting in cell growth inhibition and apoptosis. AZD7648 enhanced olaparib efficacy across a range of doses and schedules in xenograft and PDX models, enabling sustained tumour regression and providing a clear rationale for its clinical investigation. Through its differentiated mechanism of action as an NHEJ inhibitor, AZD7648 complements the current armamentarium of DDR-targeted agents and has potential in combination with these agents to achieve deeper responses to current therapies.
Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia
Authors: Dou Liping , Yan Fei , Pang Jiuxia , Zheng Dehua , Li Dandan , Gao Li , Wang Lijun , Xu Yihan , Shi Jinlong , Wang Qian , Zhou Lei , Shen Na , Singh Puja , Wang Lili , Li Yonghui , Gao Yvchi , Liu Tao , Chen Chongjian , Al-Kali Aref , Litzow Mark R. , Chi Young-In , Bode Ann M. , Liu Chunhui , Huang Haojie , Liu Daihong , Marcucci Guido , Liu Shujun , Yu Li 
Published: November 2019

AbstractThe oncogenic fusion protein AML1-ETO retains the ability of AML1 to interact with the enhancer core DNA sequences, but blocks AML1-dependent transcription. Previous studies have shown that post-translational modification of AML1-ETO may play a role in its regulation. Here we report that AML1-ETO-positive patients, with high histone lysine methyltransferase Enhancer of zeste homolog 1 (EZH1) expression, show a worse overall survival than those with lower EZH1 expression. EZH1 knockdown impairs survival and proliferation of AML1-ETO-expressing cells in vitro and in vivo. We find that EZH1 WD domain binds to the AML1-ETO NHR1 domain and methylates AML1-ETO at lysine 43 (Lys43). This requires the EZH1 SET domain, which augments AML1-ETO-dependent repression of tumor suppressor genes. Loss of Lys43 methylation by point mutation or domain deletion impairs AML1-ETO-repressive activity. These findings highlight the role of EZH1 in non-histone lysine methylation, indicating that cooperation between AML1-ETO and EZH1 and AML1-ETO site-specific lysine methylation promote AML1-ETO transcriptional repression in leukemia.
Quantitating the epigenetic transformation contributing to cholesterol homeostasis using Gaussian process
Authors: Wang Chao , Scott Samantha M. , Subramanian Kanagaraj , Loguercio Salvatore , Zhao Pei , Hutt Darren M. , Farhat Nicole Y. , Porter Forbes D. , Balch William E. 
Published: November 2019

AbstractTo understand the impact of epigenetics on human misfolding disease, we apply Gaussian-process regression (GPR) based machine learning (ML) (GPR-ML) through variation spatial profiling (VSP). VSP generates population-based matrices describing the spatial covariance (SCV) relationships that link genetic diversity to fitness of the individual in response to histone deacetylases inhibitors (HDACi). Niemann-Pick C1 (NPC1) is a Mendelian disorder caused by >300 variants in the NPC1 gene that disrupt cholesterol homeostasis leading to the rapid onset and progression of neurodegenerative disease. We determine the sequence-to-function-to-structure relationships of the NPC1 polypeptide fold required for membrane trafficking and generation of a tunnel that mediates cholesterol flux in late endosomal/lysosomal (LE/Ly) compartments. HDACi treatment reveals unanticipated epigenomic plasticity in SCV relationships that restore NPC1 functionality. GPR-ML based matrices capture the epigenetic processes impacting information flow through central dogma, providing a framework for quantifying the effect of the environment on the healthspan of the individual.
Inhibitory microcircuits for top-down plasticity of sensory representations
Authors: Wilmes Katharina Anna , Clopath Claudia 
Published: November 2019

AbstractRewards influence plasticity of early sensory representations, but the underlying changes in circuitry are unclear. Recent experimental findings suggest that inhibitory circuits regulate learning. In addition, inhibitory neurons are highly modulated by diverse long-range inputs, including reward signals. We, therefore, hypothesise that inhibitory plasticity plays a major role in adjusting stimulus representations. We investigate how top-down modulation by rewards interacts with local plasticity to induce long-lasting changes in circuitry. Using a computational model of layer 2/3 primary visual cortex, we demonstrate how interneuron circuits can store information about rewarded stimuli to instruct long-term changes in excitatory connectivity in the absence of further reward. In our model, stimulus-tuned somatostatin-positive interneurons develop strong connections to parvalbumin-positive interneurons during reward such that they selectively disinhibit the pyramidal layer henceforth. This triggers excitatory plasticity, leading to increased stimulus representation. We make specific testable predictions and show that this two-stage model allows for translation invariance of the learned representation.
ESCRT-III-driven piecemeal micro-ER-phagy remodels the ER during recovery from ER stress
Authors: Loi Marisa , Raimondi Andrea , Morone Diego , Molinari Maurizio 
Published: November 2019

AbstractThe endoplasmic reticulum (ER) produces about 40% of the nucleated cell’s proteome. ER size and content in molecular chaperones increase upon physiologic and pathologic stresses on activation of unfolded protein responses (UPR). On stress resolution, the mammalian ER is remodeled to pre-stress, physiologic size and function on activation of the LC3-binding activity of the translocon component SEC62. This elicits recov-ER-phagy, i.e., the delivery of the excess ER generated during the phase of stress to endolysosomes (EL) for clearance. Here, ultrastructural and genetic analyses reveal that recov-ER-phagy entails the LC3 lipidation machinery and proceeds via piecemeal micro-ER-phagy, where RAB7/LAMP1-positive EL directly engulf excess ER in processes that rely on the Endosomal Sorting Complex Required for Transport (ESCRT)-III component CHMP4B and the accessory AAA+ATPase VPS4A. Thus, ESCRT-III-driven micro-ER-phagy emerges as a key catabolic pathway activated to remodel the mammalian ER on recovery from ER stress.
Stepwise shifts underlie evolutionary trends in morphological complexity of the mammalian vertebral column
Authors: Jones Katrina E. , Angielczyk Kenneth D. , Pierce Stephanie E. 
Published: November 2019

AbstractA fundamental concept in evolutionary biology is that life tends to become more complex through geologic time, but empirical examples of this phenomenon are controversial. One debate is whether increasing complexity is the result of random variations, or if there are evolutionary processes which actively drive its acquisition, and if these processes act uniformly across clades. The mammalian vertebral column provides an opportunity to test these hypotheses because it is composed of serially-repeating vertebrae for which complexity can be readily measured. Here we test seven competing hypotheses for the evolution of vertebral complexity by incorporating fossil data from the mammal stem lineage into evolutionary models. Based on these data, we reject Brownian motion (a random walk) and uniform increasing trends in favor of stepwise shifts for explaining increasing complexity. We hypothesize that increased aerobic capacity in non-mammalian cynodonts may have provided impetus for increasing vertebral complexity in mammals.
Enhanced and unified anatomical labeling for a common mouse brain atlas
Authors: Chon Uree , Vanselow Daniel J. , Cheng Keith C. , Kim Yongsoo 
Published: November 2019

AbstractAnatomical atlases in standard coordinates are necessary for the interpretation and integration of research findings in a common spatial context. However, the two most-used mouse brain atlases, the Franklin-Paxinos (FP) and the common coordinate framework (CCF) from the Allen Institute for Brain Science, have accumulated inconsistencies in anatomical delineations and nomenclature, creating confusion among neuroscientists. To overcome these issues, we adopt here the FP labels into the CCF to merge the labels in the single atlas framework. We use cell type-specific transgenic mice and an MRI atlas to adjust and further segment our labels. Moreover, detailed segmentations are added to the dorsal striatum using cortico-striatal connectivity data. Lastly, we digitize our anatomical labels based on the Allen ontology, create a web-interface for visualization, and provide tools for comprehensive comparisons between the CCF and FP labels. Our open-source labels signify a key step towards a unified mouse brain atlas.
Hydrothermal alteration of andesitic lava domes can lead to explosive volcanic behaviour
Authors: Heap Michael J. , Troll Valentin R. , Kushnir Alexandra R. L. , Gilg H. Albert , Collinson Amy S. D. , Deegan Frances M. , Darmawan Herlan , Seraphine Nadhirah , Neuberg Juergen , Walter Thomas R. 
Published: November 2019

AbstractDome-forming volcanoes are among the most hazardous volcanoes on Earth. Magmatic outgassing can be hindered if the permeability of a lava dome is reduced, promoting pore pressure augmentation and explosive behaviour. Laboratory data show that acid-sulphate alteration, common to volcanoes worldwide, can reduce the permeability on the sample lengthscale by up to four orders of magnitude and is the result of pore- and microfracture-filling mineral precipitation. Calculations using these data demonstrate that intense alteration can reduce the equivalent permeability of a dome by two orders of magnitude, which we show using numerical modelling to be sufficient to increase pore pressure. The fragmentation criterion shows that the predicted pore pressure increase is capable of fragmenting the majority of dome-forming materials, thus promoting explosive volcanism. It is crucial that hydrothermal alteration, which develops over months to years, is monitored at dome-forming volcanoes and is incorporated into real-time hazard assessments.
TIP60/KAT5 is required for neuronal viability in hippocampal CA1
Authors: Urban Inga , Kerimoglu Cemil , Sakib M. Sadman , Wang Haifang , Benito Eva , Thaller Christina , Zhou Xunlei , Yan Jun , Fischer André , Eichele Gregor 
Published: November 2019

AbstractAberrant histone acetylation contributes to age-dependent cognitive decline and neurodegenerative diseases. We analyze the function of lysine acetyltransferase TIP60/KAT5 in neurons of the hippocampus using an inducible mouse model. TIP60-deficiency in the adult forebrain leads within days to extensive transcriptional dysfunction characterized by the presence of a neurodegeneration-related signature in CA1. Cell cycle- and immunity-related genes are upregulated while learning- and neuronal plasticity-related genes are downregulated. The dysregulated genes seen under TIP60-deficiency overlap with those in the well-characterized CK-p25 neurodegeneration model. We found that H4K12 is hypoacetylated at the transcriptional start sites of those genes whose expression is dampened in TIP60-deficient mice. Transcriptional dysregulation is followed over a period of weeks by activation of Caspase 3 and fragmentation of β-actin in CA1 neurites, eventually leading to severe neuronal loss. TIP60-deficient mice also develop mild memory impairment. These phenotypes point to a central role of TIP60 in transcriptional networks that are critical for neuronal viability.
Human beings as islands of stability: Monitoring body states using breath profiles
Authors: Maiti Kiran Sankar , Lewton Michael , Fill Ernst , Apolonski Alexander 
Published: November 2019

AbstractBy checking the reproducibility of conventional mid-infrared Fourier spectroscopy of human breath in a small test study (15 individuals), we found that a set of volatile organic compounds (VOC) of the individual breath samples remains reproducible at least for 18 months. This set forms a unique individual’s “island of stability” (IOS) in a multidimensional VOC concentration space. The IOS stability can simultaneously be affected by various life effects as well as the onset of a disease. Reflecting the body state, they both should have different characteristics. Namely, they could be distinguished by different temporal profiles: In the case of life effects (beverage intake, physical or mental exercises, smoking etc.), there is a non-monotonic shift of the IOS position with the return to the steady state, whereas a progressing disease corresponds to a monotonic IOS shift. As a first step of proving these dependencies, we studied various life effects with the focus on the strength and characteristic time of the IOS shift. In general, our results support homeostasis on a long time scale of months, allostasis on scales of hours to weeks or until smoke quitting for smokers, as well as resilience in the case of recovery from a disease.
Differential interaction between DARC and SDF-1 on erythrocytes and their precursors
Authors: Klei T. R. L. , Aglialoro F. , Mul F. P. J. , Tol S. , Ligthart P. C. , Seignette I. M. , Geissler J. , van den Akker E. , van Bruggen R. 
Published: November 2019

AbstractThe Duffy Antigen Receptor for Chemokines (DARC) is expressed on erythrocytes and on endothelium of postcapillary venules and splenic sinusoids. Absence of DARC on erythrocytes, but not on endothelium, is referred to as the Duffy negative phenotype and is associated with neutropenia. Here we provide evidence that stromal cell-derived factor 1 (SDF-1), the chemokine that restricts neutrophil precursors to the bone marrow, binds to erythrocyte progenitors in a DARC-dependent manner. Furthermore, we show that SDF-1 binding to DARC is dependent on the conformation of DARC, which gradually changes during erythroid development, resulting in the absence of SDF-1 binding to mature erythrocytes. However, SDF-1 binding to erythrocytes was found to be inducible by pre-treating erythrocytes with IL-8 or with antibodies recognizing specific epitopes on DARC. Taken together, these novel findings identify DARC on erythrocyte precursors as a receptor for SDF-1, which may be of interest in beginning to understand the development of neutropenia in situations where DARC expression is limited.
Selecting reference genes in RT-qPCR based on equivalence tests: a network based approach
Authors: Curis Emmanuel , Nepost Calypso , Grillault Laroche Diane , Courtin Cindie , Laplanche Jean-Louis , Etain Bruno , Marie-Claire Cynthia 
Published: November 2019

AbstractBecause quantitative reverse transcription PCR (RT-qPCR) gene expression data are compositional, amounts of quantified RNAs must be normalized using reference genes. However, the two most used methods to select reference genes (NormFinder and geNorm) ignore the compositional nature of RT-qPCR data, and often lead to different results making reliable reference genes selection difficult. We propose a method, based on all pairwise equivalence tests on ratio of gene expressions, to select genes that are stable enough to be used as reference genes among a set a candidate genes. This statistical procedure controls the error of selecting an inappropriate gene. Application to 30 candidate reference genes commonly used in human studies, assessed by RT-qPCR in RNA samples from lymphoblastoid cell lines of 14 control subjects and 26 patients with bipolar disorder, allowed to select 7 reference genes. This selection was consistent with geNorm’s ranking, less with NormFinder’s ranking. Our results provide an important fundamental basis for reference genes identification using sound statistics taking into account the compositional nature of RT-qPCR data. The method, implemented in the SARP.compo package for R (available on the CRAN), can be used more generally to prove that a set of genes shares a common expression pattern.
Hybrid classical-quantum linear solver using Noisy Intermediate-Scale Quantum machines
Authors: Chen Chih-Chieh , Shiau Shiue-Yuan , Wu Ming-Feng , Wu Yuh-Renn 
Published: November 2019

AbstractWe propose a realistic hybrid classical-quantum linear solver to solve systems of linear equations of a specific type, and demonstrate its feasibility with Qiskit on IBM Q systems. This algorithm makes use of quantum random walk that runs in $${\bf{O}}$$
O
(N log(N)) time on a quantum circuit made of $${\bf{O}}$$
O
(log(N)) qubits. The input and output are classical data, and so can be easily accessed. It is robust against noise, and ready for implementation in applications such as machine learning.
Direct observation of Thermomyces lanuginosus lipase diffusional states by Single Particle Tracking and their remodeling by mutations and inhibition
Authors: Bohr Søren S.-R. , Lund Philip M. , Kallenbach Amalie S. , Pinholt Henrik , Thomsen Johannes , Iversen Lars , Svendsen Allan , Christensen Sune M. , Hatzakis Nikos S. 
Published: November 2019

AbstractLipases are interfacially activated enzymes that catalyze the hydrolysis of ester bonds and constitute prime candidates for industrial and biotechnological applications ranging from detergent industry, to chiral organic synthesis. As a result, there is an incentive to understand the mechanisms underlying lipase activity at the molecular level, so as to be able to design new lipase variants with tailor-made functionalities. Our understanding of lipase function primarily relies on bulk assay averaging the behavior of a high number of enzymes masking structural dynamics and functional heterogeneities. Recent advances in single molecule techniques based on fluorogenic substrate analogues revealed the existence of lipase functional states, and furthermore so how they are remodeled by regulatory cues. Single particle studies of lipases on the other hand directly observed diffusional heterogeneities and suggested lipases to operate in two different modes. Here to decipher how mutations in the lid region controls Thermomyces lanuginosus lipase (TLL) diffusion and function we employed a Single Particle Tracking (SPT) assay to directly observe the spatiotemporal localization of TLL and rationally designed mutants on native substrate surfaces. Parallel imaging of thousands of individual TLL enzymes and HMM analysis allowed us to observe and quantify the diffusion, abundance and microscopic transition rates between three linearly interconverting diffusional states for each lipase. We proposed a model that correlate diffusion with function that allowed us to predict that lipase regulation, via mutations in lid region or product inhibition, primarily operates via biasing transitions to the active states.