bluuebunny/crossref_metadata_2025_split huggingface dataset:
The COP9 Signalosome Suppresses Cardiomyocyte Necroptosis
Authors: Xiao Peng , Wang Changhua , Lewno Megan T. , Wu Penglong , Li Jie , Su Huabo , Sternburg Jack O. , Liu Jinbao , Wang Xuejun 
Published: December 2019

AbstractBackgroundLoss of cardiomyocyte (CMs) due to apoptosis and regulated necrosis contributes to heart failure. However, the molecular mechanisms governing regulated CM necrosis remain obscure. The COP9 signalosome (CSN) formed by 8 unique protein subunits (COPS1 through COPS8) functions to deneddylate Cullin-RING ligases (CRLs), thereby regulating the functioning of the CRLs. Mice with CM-restricted knockout ofCops8(Cops8-cko) die prematurely, following reduced myocardial performance of autophagy and the ubiquitin-proteasome system (UPS) as well as massive CM necrosis. This study was aimed to determine the nature and underlying mechanisms of the CM necrosis in Cops8-cko mice.MethodsWe examined myocardial expression and activities of key proteins that reflect the status of the RIPK1-RIPK3 pathway, redox, and caspase 8 in Cops8-cko mice. Moreover, we used in vivo CM uptake of Evan’s blue dye (EBD) as an indicator of necrosis and performed Kaplan-Meier survival analyses to test whether treatment with a RIPK1 kinase inhibitor (necrostatin-1) or an antioxidant (N-acetyl-L-cysteine), global knockout of theRIPK3or thePpifgene, CM-restricted knockout of theNrf2gene, or cardiacHMOX1overexpression could rescue the Cops8-cko phenotype.ResultsCompared with littermate control mice, myocardial protein levels of RIPK1, RIPK3, MLKL, the RIPK1-bound RIPK3, protein carbonyls, full-length caspase 8, Nrf2, Ser40-phosphorylated Nrf2 and BCL2, as well as histochemical staining of superoxide anions were significantly increased but the cleaved caspase 8 and the overall caspase 8 activity were markedly decreased in Cops8-cko mice, indicating that the RIPK1-RIPK3 and the Nrf2 pathways are activated and caspase 8 activation is suppressed by Cops8-cko. Continuous necrostatin-1 infusion initiated at 2 weeks of age nearly completely blocked CM necrosis at 3 weeks and markedly delayed premature death of Cops8-cko mice.RIPK3haploinsufficiency or cardiac-specificNrf2heterozygous knockout discernably attenuated CM necrosis and/or delayed mouse premature death; conversely,Ppifknockout, N-acetyl-L-cysteine treatment, and cardiac overexpression of HMOX1 exacerbated CM necrosis and mouse premature death.ConclusionsCardiac Cops8/CSN malfunction causes RIPK1-RIPK3 mediated CM necroptosis in mice; sustained Nrf2 activation and reductive stress pivot cardiomyocytes to necroptosis when autophagy and the UPS are impaired; and the CSN plays an indispensable role in suppressing CM necroptosis.
Genome-wide survey of tandem repeats by nanopore sequencing shows that disease-associated repeats are more polymorphic in the general population
Authors: Mitsuhashi Satomi , Frith Martin C , Matsumoto Naomichi 
Published: December 2019

AbstractTandem repeats are highly mutable and contribute to the development of human disease by a variety of mechanisms. However, it is difficult to predict which tandem repeats may cause a disease. We performed a genome-wide survey of the millions of human tandem repeats using long read genome sequencing data from 16 humans. We found that known Mendelian disease-causing or disease-associated repeats, especially coding CAG and 5’UTR GGC repeats, are relatively long and polymorphic in the general population. This method, especially if used in GWAS, may indicate possible new candidates of pathogenic or biologically important tandem repeats in human genomes.
Expression of inhibitory checkpoint ligands by Glioblastoma Multiforme cells and the implications of an enhanced stem cell-like phenotype
Authors: Robilliard Laverne D , Joseph Wayne , Finlay Graeme , Angel Catherine E , Graham E Scott 
Published: December 2019

AbstractGlioblastoma Multiforme is a highly aggressive brain malignancy commonly refractory to classical and novel chemo-, radio- and immuno-therapies, with median survival times of ~15 months following diagnosis. Poor immunological responses exemplified by the down-regulation of T-cell activity, and upregulation of immunosuppressive cells within the tumour micro-environment have limited the effectiveness of immunotherapy in GBM to date. Here we show that GBM cells express a large repertoire of inhibitory checkpoint ligands. Furthermore, GBM cells with an enhanced stem cell-like phenotype exhibit heightened levels of inhibitory checkpoint ligands, compared to non-stem cell-like GBM cells. Understanding how GBM modulates an extensive repertoire of immune checkpoint ligands and the functional consequence on immune evasion are necessary to develop effective immuno-therapeutics.
The Potential of Lipolytic Filamentous Fungi Isolated from Landfill Soil as Poly-β-Hydroxybutirate (PHB) Bioplastic Degrader
Authors: Yanti Nur Arfa , Sriwahyuni Endang , La Omi Nur Rayani , Muhiddin Nurhayani H. , Ahmad Sitti Wirdhana 
Published: December 2019

AbstractThe present study was investigated the potential of lipolytic fungi (molds) isolated from landfill soil in degrading Poly-β-hydroxybutyrate (PHB). Screening of PHB-degrading lipolytic molds was done in two stages, such as screening of lipolytic molds which was identified by the formation of orange fluorescent halos around the colony on rhodamine B agar medium and the degradation PHB ability test was identified by the formation of clear zone around colony on PHB emulsion medium. Characterization of isolates was done based on phenotypic characters and the identification was done by numerical-phenetic analysis. Three lipolytic mold isolates that have ability in degrading PHB bioplastic i.e isolate KC1, KE1 and KE6. These molds have asexual spore form conidia, foot cell, septate hyphae, unbranched conidiophore, and spore mass located at the apex of phialid. The identification results showed that isolate KC1 is identic toAspergillus terreus, KE1 is identic toAspergillus nigerand KE6 is identic toAspergillus fumigatus.
Chromatin reorganization during myoblast differentiation involves the caspase-dependent removal of SATB2
Authors: Bell Ryan A.V. , Al-Khalaf Mohammad H. , Brunette Steve , Chu Alphonse , Dechant Georg , Apostolova Galina , Dilworth Jeffrey , Megeney Lynn A. 
Published: December 2019

SummaryInduction of lineage-specific gene programs are strongly influenced by alterations in local chromatin architecture. However, key players that impact this genome reorganization remain largely unknown. Here, we report that removal of special AT-rich binding protein 2 (SATB2), a nuclear protein that binds matrix attachment regions, is a key event in initiating myogenic differentiation. Deletion of SATB2 in muscle cell culture models and in vivo, accelerates differentiation and depletes the muscle progenitor pool, respectively. Genome wide analysis indicates that SATB2 binding is both repressive and inductive, as loss of SATB2 leads to expression of differentiation regulatory factors and inhibition of genes that impair this process. Finally, we noted that the differentiation-specific decline in SATB2 protein is dependent on a caspase 7-mediated cleavage event. Taken together, this study demonstrates that temporal control of SATB2 protein is critical for shaping the chromatin environment and coordinating the myogenic differentiation program.Graphical Abstract
Open the LID: LXRα regulates ChREBPα transactivity in a target gene-specific manner through an agonist-modulated LBD-LID interaction
Authors: Fan Qiong , Nørgaard Rikke C. , Grytten Ivar , Ness Cecilie M. , Lucas Christin , Vekterud Kristin , Soedling Helen , Matthews Jason , Lemma Roza B. , Gabrielsen Odd S. , Bindesbøll Christian , Ulven Stine M. , Nebb Hilde I. , Grønning-Wang Line M. , Sæther Thomas 
Published: December 2019

ABSTRACTThe cholesterol-sensing nuclear receptor liver X receptor (LXR) and the glucose-sensing transcription factor carbohydrate responsive element-binding protein (ChREBP) are central players in regulating glucose and lipid metabolism in liver. We have previously shown that LXR regulates ChREBP transcription and activity; however, the underlying mechanisms are unclear. In the current study, we demonstrate that LXRα and ChREBPα interact physically, and show a high co-occupancy at regulatory regions in the mouse genome. LXRα co-activates ChREBPα, and regulates ChREBP-specific target genesin vitroandin vivo. This co-activation is dependent on functional recognition elements for ChREBP, but not for LXR, indicating that ChREBPα recruits LXRα to chromatin intrans. The two factors interact via their key activation domains; ChREBPα’s low glucose inhibitory domain (LID) and the ligand-binding domain (LBD) of LXRα. While unliganded LXRα co-activates ChREBPα, ligand-bound LXRα surprisingly represses ChREBPα activity on ChREBP-specific target genes. Mechanistically, this is due to a destabilized LXRα:ChREBPα interaction, leading to reduced ChREBP-binding to chromatin and restricted activation of glycolytic and lipogenic target genes. This ligand-driven molecular switch highlights an unappreciated role of LXRα that was overlooked due to LXR lipogenesis-promoting function.
Partial loss of colonic primary cilia promotes inflammation and carcinogenesis
Authors: Tang Ruizhi , Paul Conception , Lattanzio Rossano , Eguether Thibaut , Tulari Hulya , Bremond Julie , Maurizy Chloé , Poupeau Sophie , Turtoi Andrei , Svrcek Magali , Seksik Philippe , Castronovo Vincent , Delvenne Philippe , Lemmers Bénédicte , Janke Carsten , Pinet Valérie , Hahne Michael 
Published: December 2019

AbstractPrimary cilia (PC) are important signaling hubs in cells and their deregulation has been associated with various diseases including cancer. Here we explored the role of PC in colorectal cancer (CRC) and colitis. In the colon we found PC to be mostly present on different subtypes of fibroblasts. Colons of mice exposed to either chemically induced colitis-associated colon carcinogenesis (CAC) or dextran sodium sulfate (DSS)-induced colitis had decreased numbers of PC. We employed conditional knock-out strains for the PC essential genes,Kif3AandIft88, to generate mice with reduced numbers of PC on colonic fibroblasts. These mice showed an increased susceptibility in the CAC model as well as in DSS-induced colitis. Colons from DSS-treated mice with PC-deficiency on fibroblasts displayed an elevated production of the pro-inflammatory cytokine IL-6 and colonic epithelial cells had diminished levels of HES-1, a key transcription factor of Notch signaling. Notably, an analysis of PC presence on biopsies of patients with ulcerative colitis as well as CRC patients revealed decreased numbers of PC on colonic fibroblasts in pathological versus surrounding normal tissue. Taken together, we provide evidence that a decrease in colonic PC numbers promotes colitis and CRC.Graphical Abstract
TIP5 safeguards genome architecture of ground-state pluripotent stem cells
Authors: Dalcher Damian , Tan Jennifer Yihong , Bersaglieri Cristiana , Peña-Hernández Rodrigo , Vollenweider Eva , Zeyen Stefan , Schmid Marc W. , Bianchi Valerio , Butz Stefan , Kuzyakiv Rostyslav , Baubec Tuncay , Marques Ana Claudia , Santoro Raffaella 
Published: December 2019

AbstractChromosomes have an intrinsic tendency to segregate into compartments, forming long-distance contacts between loci of similar chromatin states. However, how genome compartmentalization is regulated remains elusive. We analyzed two closely and developmentally related pluripotent cell types: ground-state ESCs that have an open and active chromatin and developmentally advanced ESCs that display a more closed and repressed state. We show that these two ESC types differ in their regulation of genome organization due to their differential dependency on TIP5, a component of the chromatin remodeling complex NoRC. We show that TIP5 interacts on ESC chromatin with SNF2H, DNA topoisomerase 2A (TOP2A) and cohesin. TIP5 associates with sub-domains within the active A compartment that strongly intersect through long-range contacts in ESCs. We found that only ground-state chromatin requires TIP5 to limit the invasion of active domains into repressive compartments. Depletion of TIP5 increased chromatin accessibility particularly at B compartments and decreased their repressive features. Furthermore, TIP5 acts as a barrier for the repressive H3K27me3 spreading, a process that also requires TOP2A activity. Finally, ground-state ESCs require TIP5 for growth, differentiation capacity, and correct expression of developmental genes. Our results revealed the propensity of open and active chromatin domains to invade repressive domains, an action counteracted by chromatin remodeling and the relief of chromatin torsional stress. This effort in controlling open/active chromatin domains is required to establish active and repressed genome partitioning and preserves cell function and identity.
Postnatal Expansion, Maturation and Functionality of MR1T Cells in Humans
Authors: Swarbrick Gwendolyn M. , Gela Anele , Cansler Meghan E. , Null Megan D. , Duncan Rowan B. , Nemes Elisa , Shey Muki , Nsereko Mary , Mayanja-Kizza Harriet , Kiguli Sarah , Koh Jeffrey , Hanekom Willem A. , Hatherill Mark , Lancioni Christina , Lewinsohn David M. , Scriba Thomas J. , Lewinsohn Deborah A. 
Published: December 2019

AbstractMR1-restricted T (MR1T) cells are defined by their recognition of metabolite antigens presented by the monomorphic MHC class 1-related molecule, MR1, the most highly conserved MHC class I related molecule in mammalian species. Mucosal-associated invariant T (MAIT) cells are the predominant subset of MR1T cells expressing an invariant TCR α-chain, TRAV1-2. These cells comprise a T cell subset that recognizes and mediates host immune responses to a broad array of microbial pathogens, includingMycobacterium tuberculosis. Here, we sought to characterize development of circulating human MR1T cells as defined by MR1-5-OP-RU tetramer labelling and of the TRAV1-2+MAIT cells defined by expression of TRAV1-2 and high expression of CD26 and CD161 (TRAV1-2+CD161++CD26++cells). We analysed postnatal expansion, maturation and functionality of peripheral blood MR1-5-OP-RU tetramer+MR1T cells in cohorts from three different geographic settings with different tuberculosis (TB) vaccination practices, levels of exposure to and infection withM. tuberculosis.Early after birth, frequencies of MR1-5-OP-RU tetramer+MR1T cells increased rapidly by several fold. This coincided with the transition from a predominantly CD4+and TRAV1-2−population in neonates, to a predominantly TRAV1-2+CD161++CD26++CD8+population. We also observed that tetramer+MR1T cells that expressed TNF upon mycobacterial stimulation were very low in neonates, but increased ∼10-fold in the first year of life. These functional MR1T cells in all age groups were MR1-5-OP-RU tetramer+TRAV1-2+and highly expressed CD161 and CD26, markers that appeared to signal phenotypic and functional maturation of this cell subset. This age-associated maturation was also marked by the loss of naïve T cell markers on tetramer+TRAV1-2+MR1T cells more rapidly than tetramer+TRAV1-2−MR1T cells and non-MR1T cells. These data suggest that neonates have infrequent populations of MR1T cells with diverse phenotypic attributes; and that exposure to the environment rapidly and preferentially expands the MR1-5-OP-RU tetramer+TRAV1-2+population of MR1T cells, which becomes the predominant population of functional MR1T cells early during childhood.
Skin microbiota dynamics of dairy cows affected by digital dermatitis
Authors: Ariza Juan Manuel , Döpfer Dörte , Oberle Kenny , Anklam Kelly , Labrut Sophie , Bareille Nathalie , Relun Anne , Guatteo Raphaël 
Published: December 2019

AbstractBovine digital dermatitis (DD), is a highly prevalent disease among dairy cattle characterized by ulcerative and painful lesions. While multiple management factors are involved in the disease, its precise etiology remains uncertain and the effectiveness of current control strategies remains highly variable. The major role ofTreponemaspp. in the development of the disease is consistently recognized. Nevertheless, it remains unclear how other bacterial communities are relevant to the onset and progression of the disease, and how the skin microbiota is affected by the environment during the course of the disease. The objective of this study was to describe the dynamics of microbiota recovered from DD affected feet under field conditions. This study described the diversity, structure, and composition of DD lesion microbiota over 45 days according to different clinical and management factors. The results of this investigation confirmed the existence of a specific skin microbiota associated with DD lesions, dominated byTreponemaspp. and very different from the microbiota of healthy skin. Interestingly, the diversity and structure of the microbiota in DD lesions did not vary with the footbath disinfectant or the individual topical antibiotic treatments used. In addition, microbiotas from proliferative lesions evidenced a different structure and diversity in comparison to non-proliferative lesions. Our results confirm the major role ofTreponemaspp. And highlight the potential role ofMycoplasmopsisspp. in the DD lesion onset. Further studies are needed to confirm whether the clinical course of DD lesions is driven by a particular microbiota and how that microbiota may induce disease.HighlightsMultiple bacteria have been identified in DD lesions. However, many of these microorganisms are inhabitants of the foot skin and the farm environment. For the first time, the microbiota of DD lesions was monitored for 45 days under field conditions to describe its evolution over time. The results of this investigation highlighted a particular microbiota dominated byTreponemaspp. present on the skin of DD affected animals and highly different from those microbiotas of healthy skin. The microbiota of DD lesions evolved over the study period and differential bacteria were identified. Further studies are warranted to determine the role of the bacteria composing these microbiotas on lesion onset and outcome.
Frontopolar cortex is a mediator of network modularity in the primate brain
Authors: Wu Zhemeng , Ainsworth Matthew , Browncross Helen , Bell Andrew H. , Buckley Mark J. 
Published: December 2019

AbstractPrimate frontopolar cortex (FPC), occupied by area 10, sits atop a functional hierarchy of prefrontal cortical regions yet little is known about its causal role influencing cognition and brain networks. We studied resting-state-functional-connectivity (rsfc) networks in rhesus monkeys with or without FPC; 86 cortical regions showed significant differences in inter-area rsfc measures in lesioned animals versus controls. K-means clustering showed these regions were organized into two distinct networks in lesioned animals, whereas the same areas clustered into four networks in control animals. These networks extended within and beyond prefrontal cortex. These results suggest that FPC is involved in mediating cortical networks in the primate brain, both within and beyond prefrontal cortex. Even after 40 months only partial recovery of lesion-induced reduced modularity had occurred. We therefore suggest that FPC might help implement long-standing diverse neural network dynamics.
Image Reconstruction Reveals the Impact of Aging on Face Perception
Authors: Chang Chi-Hsun , Nemrodov Dan , Drobotenko Natalia , Nestor Adrian , Lee Andy C. H. 
Published: December 2019

AbstractExtensive work has demonstrated a decline in face recognition abilities associated with healthy aging. To date, however, there has been limited insight into the nature and the extent of aging-related alterations in internal face representations. Here, we sought to address these issues by using an image reconstruction approach that capitalizes on the structure of behavioral data to reveal the pictorial content of visual representations. To this end, healthy young and older adults provided similarity judgments with pairs of face images. Facial shape and surface features were subsequently derived from the structure of the data for each participant and combined into image reconstructions of facial appearance. Our findings revealed that image reconstruction was successful for every participant, irrespective of age. However, reconstruction accuracies of shape and surface information were lower for older individuals than young individuals. Specifically, facial features diagnostic for face perception, such as eye shape and skin tone, were reconstructed poorly in older adults relative to young adults. At the same time, we found that age-related effects only accounted for a relatively small proportion of individual variability in face representations. Thus, our results provide novel insight into age-related changes in visual perception, they account for the decline in facial recognition occurring with age and they demonstrate the utility of image reconstruction to uncovering internal representations across a variety of populations.
Susceptible host availability modulates climate effects on dengue dynamics
Authors: Nova Nicole , Deyle Ethan R. , Shocket Marta S. , MacDonald Andrew J. , Childs Marissa L. , Rypdal Martin , Sugihara George , Mordecai Erin A. 
Published: December 2019

AbstractExperiments and models suggest that climate affects mosquito-borne disease transmission. However, disease transmission involves complex nonlinear interactions between climate and population dynamics, which makes detecting climate drivers at the population level challenging. By analyzing incidence data, estimated susceptible population size, and climate data with methods based on nonlinear time series analysis (collectively referred to as empirical dynamic modeling), we identified drivers and their interactive effects on dengue dynamics in San Juan, Puerto Rico. Climatic forcing arose only when susceptible availability was high: temperature and rainfall had net positive and negative effects, respectively. By capturing mechanistic, nonlinear, and context-dependent effects of population susceptibility, temperature, and rainfall on dengue transmission empirically, our model improves forecast skill over recent, state-of-the-art models for dengue incidence. Together, these results provide empirical evidence that the interdependence of host population susceptibility and climate drive dengue dynamics in a nonlinear and complex, yet predictable way.