bluuebunny/crossref_metadata_2025_split huggingface dataset:
In depth analysis of kinase cross screening data to identify CAMKK2 inhibitory scaffolds
Authors: O’Byrne Sean N. , Scott John W. , Pilotte Joseph R. , Santiago André de S. , Langendorf Christopher G. , Oakhill Jonathan S. , Eduful Benjamin J. , Couñago Rafael M. , Wells Carrow I. , Zuercher William J. , Willson Timothy M. , Drewry David H. 
Published: January 2020

AbstractThe calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) plays a central role in many cell signaling pathways. CAMKK2 activates CAMK1, CAMK4, AMPK, and AKT leading to numerous physiological responses. Deregulation of CAMKK2 is linked to several diseases, suggesting utility of CAMKK2 inhibitors for oncological, metabolic and inflammatory indications. In this work we review the role of CAMKK2 in biology and disease. Through analysis of literature and public databases we have identified starting points for CAMKK2 inhibitor medicinal chemistry campaigns. These starting points provide an opportunity for the development of selective CAMKK2 inhibitors and will lead to tools that delineate the roles of this kinase in disease biology.
Life histories and niche dynamics in late Quaternary proboscideans from Midwestern North America: evidence from stable isotope analyses
Authors: Widga Chris , Hodgins Greg , Kolis Kayla , Lengyel Stacey , Saunders Jeff , Walker J. Douglas , Wanamaker Alan D. 
Published: January 2020

ABSTRACTStable isotopes of mammoths and mastodons have the potential to illuminate ecological changes in late Pleistocene landscapes and megafaunal populations as these species approached extinction. The ecological factors at play in this extinction remain unresolved, but isotopes of bone collagen (δ13C, δ15N) and tooth enamel (δ13C, δ18O,87Sr/86Sr) from the Midwest, USA are leveraged to examine ecological and behavioral changes that occurred during the last interglacial-glacial cycle. Both species had significant C3 contributions to their diets and experienced increasing levels of niche overlap as they approached extinction. A subset of mastodons after the last glacial maximum (LGM) exhibit low δ15N values that may represent expansion into a novel ecological niche, perhaps densely occupied by other herbivores. Stable isotopes from serial and micro-sampled enamel show increasing seasonality and decreasing temperatures as mammoths transitioned from Marine Isotope Stage (MIS) 5e to glacial conditions (MIS 4, MIS 3, MIS 2). Isotopic variability in enamel suggests mobility patterns and life histories have potentially large impacts on the interpretation of their stable isotope ecology. This study further refines the ecology of midwestern mammoths and mastodons demonstrating increasing seasonality and niche overlap as they responded to landscape changes in the final millennia before extinction.
Over-Confluence of expanded bone marrow mesenchymal stem cells ameliorates their chondrogenic capacity in 3D cartilage tissue engineering
Authors: Tucker Damien , Still Karen , Blom Ashley , Hollander Anthony P. , Kafienah Wael 
Published: January 2020

ABSTRACTCartilage tissue engineering using bone marrow-derived mesenchymal stem cells (BM-MSCs) is a growing technology for the repair of joint defects. Culturing BM-MSCs to over confluence has historically been avoided due to perceived risk to cell viability, growth inhibition and differentiation potential. Here we show that a simple change in culture practice, based on mimicking the condensation phase during embryonic cartilage development, results in biochemically and histologically superior cartilage tissue engineered constructs. Whole transcriptome analysis of the condensing cells revealed a phenotype associated with early commitment to chondrogenic precursors. This simple adjustment to the common stem cell culture technique would impact the quality of all cartilage tissue engineering modalities utilising these cells.
Regulation of canonical Wnt signalling by the ciliopathy protein MKS1 and the E2 ubiquitin-conjugating enzyme UBE2E1
Authors: Szymanska Katarzyna , Boldt Karsten , Logan Clare V. , Adams Matthew , Robinson Philip A. , Ueffing Marius , Zeqiraj Elton , Wheway Gabrielle , Johnson Colin A. 
Published: January 2020

AbstractA functional primary cilium is essential for normal and regulated signalling. Primary ciliary defects cause a group of developmental conditions known as ciliopathies, but the precise mechanisms of signal regulation by the cilium remain unclear. Previous studies have implicated the ubiquitin proteasome system (UPS) in regulation of Wnt signalling at the ciliary basal body. Here, we provide mechanistic insight into ciliary ubiquitin processing in cells and for a ciliopathy mouse model lacking the ciliary protein Mks1.In vivoloss of Mks1 sensitizes cells to proteasomal disruption, leading to abnormal accumulation of ubiquitinated proteins. To substantiate a direct link between MKS1 and the UPS, we identified UBE2E1, an E2 ubiquitin-conjugating enzyme that polyubiquitinates β-catenin, and RNF34, an E3 ligase, as novel interactants of MKS1. UBE2E1 and MKS1 colocalized, particularly during conditions of ciliary resorption, and loss of UBE2E1 recapitulates the ciliary and Wnt signalling phenotypes observed during loss of MKS1. Levels of UBE2E1 and MKS1 are co-dependent and UBE2E1 mediates both regulatory and degradative ubiquitination of MKS1. Furthermore, we demonstrate that processing of phosphorylated β-catenin occurs at the ciliary base through the functional interaction between UBE2E1 and MKS1. These observations suggest that correct β-catenin levels are tightly regulated at the primary cilium by a ciliary-specific E2 (UBE2E1) and a regulatory substrate-adaptor (MKS1), confirming the fundamental role of UPS defects in the molecular pathogenesis of ciliopathies.
Modeling the immunological pre-adaptation of HIV-1
Authors: van Dorp Christiaan H. , van Boven Michiel , de Boer Rob J. 
Published: January 2020

AbstractIt is becoming increasingly evident that the evolution of HIV-1 is to a large extent determined by the immunological background of the host. On the population-level this results in associations between specific human leukocyte antigen (HLA) alleles and polymorphic loci of the virus. Furthermore, some HLA alleles that were previously associated with slow progression to AIDS have been shown to lose their protective effect, because HLA-specific immunological escape variants have spread through the population. This phenomenon is known as immunological pre-adaptation. Apart from adapting to human immune responses, the set-point virus load (SPVL) of HIV-1 is thought to have evolved to values that optimize the population-level fitness of the virus. This suggestion is supported by considerable heritability of the SPVL. Previous modeling studies show that whether or not SPVL optimization is expected to occur depends sensitively on the underlying assumptions with respect to the extent of within-versus between-host selection. Here we use a detailed and semi-realistic multi-level HIV-1 model in which immunological pre-adaptation and SPVL evolution can emerge from the underlying interactions of the virus with the immune system of the host. This enables us to study the effect of immunological escape on disease progression, and how disease progression may be molded by SPVL evolution. We find that the time to AIDS could decrease significantly (0.5-1.0 years) in a HLA-dependent manner by immunological pre-adaptation over the long-term course of the epidemic (> 100 years). We find that SPVL is not expected to evolve to optimize the population-level fitness of HIV-1, even though high heritability of the SPVL emerges from continual selection of immune-escape mutations.
Inferring Disease-Associated Piwi-Interacting RNAs via Graph Attention Networks
Authors: Zheng Kai , You Zhu-Hong , Wang Lei , Wong Leon , Chen Zhan-Heng , Jiang Han-Jing 
Published: January 2020

ABSTRACTMotivationPIWI proteins and Piwi-Interacting RNAs (piRNAs) are commonly detected in human cancers, especially in germline and somatic tissues, and correlates with poorer clinical outcomes, suggesting that they play a functional role in cancer. As the problem of combinatorial explosions between ncRNA and disease exposes out gradually, new bioinformatics methods for large-scale identification and prioritization of potential associations are therefore of interest. However, in the real world, the network of interactions between molecules is enormously intricate and noisy, which poses a problem for efficient graph mining. This study aims to make preliminary attempts on bionetwork based graph mining.ResultsIn this study, we present a method based on graph attention network to identify potential and biologically significant piRNA-disease associations (PDAs), called GAPDA. The attention mechanism can calculate a hidden representation of an association in the network based on neighbor nodes and assign weights to the input to make decisions. In particular, we introduced the attention-based Graph Neural Networks to the field of bio-association prediction for the first time, and proposed an abstract network topology suitable for small samples. Specifically, we combined piRNA sequence information and disease semantic similarity with piRNA-disease association network to construct a new attribute network. In the experiment, GAPDA performed excellently in five-fold cross-validation with the AUC of 0.9038. Not only that, but it still has superior performance compared to methods based on collaborative filtering and attribute features. The experimental results show that GAPDA ensures the prospect of the graph neural network on such problems and can be an excellent supplement for future biomedical research.Contactzhuhongyou@ms.xjb.ac.cn;leiwang@ms.xjb.ac.cnSupplementary informationSupplementary data are available at Bioinformatics online.
Convergent Met and voltage-gated Ca2+channel signaling on Ras-Erk MAPK drives migratory activation of dendritic cells parasitized byToxoplasma gondii
Authors: Ólafsson Einar B. , ten Hoeve Arne L. , Wang Xiaoze Li , Westermark Linda , Varas-Godoy Manuel , Barragan Antonio 
Published: January 2020

AbstractRas-Erk MAPK signaling controls many of the principal pathways involved in metazoan cell motility, drives metastasis of multiple cancer types and is targeted in chemotherapy. Yet, its putative roles in immune cell functions or in infections have remained elusive. Here, using primary dendritic cells (DCs) in an infection model with the protozoanToxoplasma gondii, we show that two pathways activated by infection converge on Ras-Erk MAPK signaling to promote migration of parasitized DCs. We identify signaling through the receptor tyrosine kinase Met (also known as HGFR) as a driver ofT. gondii-induced DC hypermotility. Further, we show that voltage-gated Ca2+channel (VGCC, subtype CaV1.3) signaling impacts the migratory activation of DCs via calmodulin-calmodulin kinase II. We report that VGCC and Met signaling converge on Ras GTPase to drive Erk1/2 phosphorylation and migratory activation ofT. gondii-infected DCs. The data provide a molecular basis for the hypermigratory mesenchymal-to-amoeboid transition (MAT) of parasitized DCs. The emerging concept suggests that parasitized DCs acquire metastasis-like migratory properties to promote infection-related dissemination.
Does seed mass drive interspecies variation in the effect of management practices on weed demography?
Authors: Elena Kazakou , Guillaume Fried , Pierre-Olivier Cheptou , Olivier Gimenez 
Published: January 2020

AbstractOptimizing the effect of management practices on weed population dynamics is challenging due to the difficulties in inferring demographic parameters in seed banks and their response to disturbance. Here, we used a long-term plant survey between 2006 and 2012 in 46 French vineyards and quantified the effects of management practices (tillage, mowing and herbicide) on colonization, germination and seed survival of 30 weed species in relation to their seed mass. To do so, we used a recent statistical approach to reliably estimate demographic parameters for plant populations with a seed bank using time series of presence–absence data, which we extended to account for interspecies variation in the effects of management practices on demographic parameters. Our main finding was that when the level of disturbance increased (i.e., in plots with a higher number of herbicide, tillage or mowing treatments), colonization and survival in large-seeded species increased faster than in small-seeded species. High disturbance through tillage increased survival in the seed bank of species with high seed mass. The application of herbicides, considered as an intermediate disturbance, increased germination, survival and colonization probabilities of species with high seed mass. Mowing, representing habitats more competitive for light, increased the survival of species with high seed mass. Overall, the strong relationships between the effects of management practices and seed mass provides an indicator for predicting the dynamics of weed communities under disturbance.
Microbial diversity characterization of seawater in a pilot study using Oxford Nanopore Technologies long-read sequencing
Authors: Liem M. , Regensburg-Tuïnk A.J.G. , Henkel C.V. , Spaink H.P. 
Published: January 2020

ABSTRACTCurrently the majority of non-culturable microbes in sea water are yet to be discovered, Nanopore offers a solution to overcome the challenging tasks to identify the genomes and complex composition of oceanic microbiomes. In this study we evaluate the utility of Oxford Nanopore Technologies (ONT) sequencing to characterize microbial diversity in seawater from multiple locations. We compared the microbial species diversity of retrieved environmental samples from two different locations and time points. With only three ONT flow cells we were able to identify thousands of organisms, including bacteriophages, from which a large part at species level. It was possible to assemble genomes from environmental samples with Flye. In several cases this resulted in >1 Mbp contigs and in the particular case of a Thioglobus singularis species it even produced a near complete genome. k-mer analysis reveals that a large part of the data represents species of which close relatives have not yet been deposited to the database. These results show that our approach is suitable for scalable genomic investigations such as monitoring oceanic biodiversity and provides a new platform for education in biodiversity
Dissecting the roles of GRK2 and GRK3 in μ-opioid receptor internalization and β-arrestin2 recruitment using CRISPR/Cas9-edited HEK293 cells
Authors: Møller Thor C. , Pedersen Mie F. , van Senten Jeffrey R. , Seiersen Sofie D. , Mathiesen Jesper M. , Bouvier Michel , Bräuner-Osborne Hans 
Published: January 2020

AbstractMost G protein-coupled receptors (GPCRs) recruit β-arrestins and internalize upon agonist stimulation. For the μ-opioid receptor (μ-OR), this process has been linked to development of opioid tolerance. GPCR kinases (GRKs), particularly GRK2 and GRK3, have been shown to be important for μ-OR recruitment of β-arrestin and internalization. However, the contribution of GRK2 and GRK3 to β-arrestin recruitment and receptor internalization, remain to be determined in their complete absence. Using CRISPR/Cas9-mediated genome editing we established HEK293 cells with knockout of GRK2, GRK3 or both to dissect their individual contributions in β-arrestin2 recruitment and μ-OR internalization upon stimulation with four different agonists. We showed that GRK2/3 removal reduced agonist-induced μ-OR internalization and β-arrestin2 recruitment substantially and we found GRK2 to be more important for these processes than GRK3. Furthermore, we observed a sustained and GRK2/3 independent component of β-arrestin2 recruitment to the plasma membrane upon μ-OR activation. Rescue expression experiments restored GRK2/3 functions. Inhibition of GRK2/3 using the small molecule inhibitor CMPD101 showed a high similarity between the genetic and pharmacological approaches, cross-validating the specificity of both. However, off-target effects were observed at high CMPD101 concentrations. These GRK2/3 KO cell lines should prove useful for a wide range of studies on GPCR function.
Abdominal symptoms during primary Sjögren’s syndrome: a prospective study
Authors: Parreau Simon , Jacques Jérémie , Dumonteil Stéphanie , Palat Sylvain. , Geyl Sophie , Gondran Guillaume , Bezanahary Holy , Liozon Eric , Azaïs Julie , Colombie Stéphanie , Jauberteau Marie-Odile , Loustaud-Ratti Véronique , Ly Kim-Heang , Fauchais Anne-Laure 
Published: January 2020

AbstractContextAbdominal symptoms are poorly documented during primary Sjögren’s syndrome (pSS).ObjectivesTo describe abdominal symptoms among pSS patients and to assess their association with characteristics of the disease.MethodsOne hundred and fifty patients followed at Hospital and University Center of Limoges were prospectively included and were evaluated using a composite global symptom score (GSS) describing abdominal symptoms and their severity. Data concerning the clinical and biological characteristics of the pSS and abdominal disorders were also collected.ResultsNinety-five per cent of pSS patients suffered from abdominal symptoms with a median GSS of 7.5±5.5 points out of 30. More than half of the patients experienced abdominal tension (68%), upper abdominal pain (54%), abdominal discomfort (58%) and/or constipation (54%). Regarding the pSS activity ESSDAI score items, general and central nervous system involvement was associated with a high GSS. Regarding the patients’ symptoms ESSPRI score, there was a positive correlation with the GSS (p<0.01). Multivariate analysis showed a statistical association between a high GSS and seronegative status for SSA, gastroparesis and ESSPRI score (p<0.01for each one).ConclusionThis study revealed that more than 90% of pSS patients suffered from abdominal symptoms. There is currently no therapeutic recommendation because of the lack of specific study and comprehension of the physiopathological mechanisms involved.
NvPOU4/Brain3functions as a terminal selector gene in the nervous system of the cnidarianNematostella vectensis
Authors: Tournière Océane , Dolan David , Richards Gemma Sian , Sunagar Kartik , Columbus-Shenkar Yaara Y , Moran Yehu , Rentzsch Fabian 
Published: January 2020

SUMMARYTerminal selectors are transcription factors that control the morphological, physiological and molecular features that characterize distinct cell types. Here we use expression analyses and a transgenic reporter line to show thatNvPOU4is expressed in post-mitotic cells that give rise to a diverse set of neural cell types in the sea anemoneNematostella vectensis. We generated a loss-of-function allele by CRISPR/Cas9 and used additional transgenic reporter lines to show that the initial specification of neural cells is not affected in theNvPOU4mutants. Analyses of transcriptomes derived from the mutants and from different neural cell populations revealed thatNvPOU4is required for the execution of the terminal differentiation program of these neural cells. These findings suggest that POU4 genes have ancient functions as terminal selectors for morphologically and functionally highly disparate types of neurons and they provide experimental support for the relevance of terminal selectors for understanding the evolution of cell types.
A new long-read RNA-seq analysis approach identifies and quantifies novel transcripts of very large genes
Authors: Uapinyoying Prech , Goecks Jeremy , Knoblach Susan M. , Panchapakesan Karuna , Bonnemann Carsten G , Partridge Terence A. , Jaiswal Jyoti K , Hoffman Eric P. 
Published: January 2020

ABSTRACTRNA-seq is widely used for studying gene expression, but commonly used sequencing platforms produce short reads that only span up to two exon-junctions per read. This makes it difficult to accurately determine the composition and phasing of exons within transcripts. Although long-read sequencing improves this issue, it is not amenable to precise quantitation, which limits its utility for differential expression studies. We used long-read isoform sequencing combined with a novel analysis approach to compare alternative splicing of large, repetitive structural genes in muscles. Analysis of muscle structural genes that produce medium (Nrap−5kb), large (nebulin - 22 kb) and very-large (titin - 106 kb) transcripts in cardiac muscle, and fast and slow skeletal muscles identified unannotated exons for each of these ubiquitous muscle genes. This also identified differential exon usage and phasing for these genes between the different muscle types. By mapping the in-phase transcript structures to known annotations, we also identified and quantified previously unannotated transcripts. Results were confirmed by endpoint PCR and Sanger sequencing, which revealed muscle-type specific differential expression of these novel transcripts. The improved transcript identification and quantification demonstrated by our approach removes previous impediments to studies aimed at quantitative differential expression of ultra-long transcripts.
cGAS, a DNA Sensor, Promotes Inflammatory Responses in Huntington Disease
Authors: Sharma Manish , Rajendrarao Sumitha , Shahani Neelam , Ramĺrez-Jarquĺn Uri Nimrod , Subramaniam Srinivasa 
Published: January 2020

AbstractThe genetic cause of Huntington disease (HD) is attributed to the N-terminal polyglutamine expansion of huntingtin (mHTT). mHTT, which is a ubiquitously expressed protein, induces noticeable damage to the striatum, which affects motor, psychiatric, and cognitive functions in HD individuals. Although inflammatory responses apparently precede striatal damage and an overall progression of HD, the molecular mechanisms at work remain unclear (1-6). In this study, we found that cyclic GMP-AMP synthase (cGAS), a DNA sensor, which regulates inflammation, autophagy, and cellular senescence (7-9), plays a critical role in the inflammatory responses of HD. Ribosome profiling analysis reveals thatcGAS mRNAhas a high ribosome occupancy at exon 1 and codon-specific pauses at positions 171 (CCG) and 172 (CGT) in HD cells, compared to the control, indicating an altered cGAS expression. Accordingly, cGAS protein levels and activity, as measured by phosphorylation of stimulator of interferon genes (STING) or TANK-binding kinase 1 (TBK1), are increased in HD striatal cells, mouse Q175HD striatum and human postmortem HD striatum, compared to the healthy control. Furthermore, cGAS-dependent inflammatory genes such asCxcl10andCcl5show enhanced ribosome occupancy at exon 3 and exon 1, respectively and are upregulated in HD cells. Depletion of cGAS via CRISPR/Cas-9 diminishes cGAS activity and decreases expression of inflammatory genes while suppressing the autophagy upregulation in HD cells. We additionally detected the presence of numerous micronuclei, a known inducer of cGAS, in the cytoplasm of HD cells. Overall, the data indicates that cGAS is highly upregulated in HD and mediates inflammatory and autophagy responses. Thus, targeting cGAS may offer therapeutic benefits in HD.