bluuebunny/crossref_metadata_2025_split huggingface dataset:
Co-Phosphorylation Networks Reveal Subtype-Specific Signaling Modules in Breast Cancer
Authors: Ayati Marzieh , Chance Mark R , Koyutürk Mehmet 
Published: May 2020

AbstractMotivationProtein phosphorylation is a ubiquitous mechanism of post-translational modification that plays a central role in cellular signaling. Phosphorylation is particularly important in the context of cancer, as down-regulation of tumor suppressors and up-regulation of oncogenes by the dysregulation of associated kinase and phosphatase networks are shown to have key roles in tumor growth and progression. Despite recent advances that enable large-scale monitoring of protein phosphorylation, these data are not fully incorporated into such computational tasks as phenotyping and subtyping of cancers.ResultsWe develop a network-based algorithm, CoPPNet, to enable unsupervised subtyping of cancers using phosphorylation data. For this purpose, we integrate prior knowledge on evolutionary, structural, and functional association of phosphosites, kinase-substrate associations, and protein-protein interactions with the correlation of phosphorylation of phosphosites across different tumor samples (a.k.a co-phosphorylation) to construct a context-specific weighted network of phosphosites. We then mine these networks to identify subnetworks with correlated phosphorylation patterns. We apply the proposed framework to two mass-spectrometry based phosphorylation datasets for breast cancer, and observe that (i) the phosphorylation pattern of the identified subnetworks are highly correlated with clinically identified subtypes, and (ii) the identified subnetworks are highly reproducible across datasets that are derived from different studies. Our results show that integration of quantitative phosphorylation data with network frameworks can provide mechanistic insights into the differences between the signaling mechanisms that drive breast cancer subtypes. Furthermore, the reproducibility of the identified subnetworks suggests that phosphorylation can provide robust classification of disease response and markers.Availability and implementationCoPPNetis available athttp://compbio.case.edu/coppnet/
Ilaprazole and other novel prazole-based compounds that bind Tsg101 inhibit viral budding of HSV-1/2 and HIV from cells
Authors: Leis Jonathan , Luan Chi-Hao , Audia James E. , Dunne Sara F. , Heath Carissa M. 
Published: May 2020

AbstractIn many enveloped virus families, including HIV and HSV, a crucial, yet unexploited, step in the viral life cycle is releasing particles from the infected cell membranes. This release process is mediated by host ESCRT complex proteins, which is recruited by viral structural proteins and provides the mechanical means for membrane scission and subsequent viral budding. The prazole drug, tenatoprazole, was previously shown to bind to ESCRT complex member Tsg101 and quantitatively block the release of infectious HIV-1 from cells in culture. In this report we show that tenatoprazole and a related prazole drug, ilaprazole, effectively block infectious Herpes Simplex Virus (HSV)-1/2 release from Vero cells in culture. By electron microscopy, we found that both prazole drugs block the release of HSV particles from the cell nuclear membrane resulting in their accumulation in the nucleus. Ilaprazole also quantitatively blocks the release of HIV-1 from 293T cells with an EC50of 0.8 μM, which is more potent than tenatoprazole. Finally, we synthesized and tested multiple novel prazole-based analogs that demonstrate both binding to Tsg101 and inhibition of viral egress in the nanomolar range of HIV-1 from 293T cells. Our results indicate that prazole-based compounds may represent a class of drugs with potential to be broad-spectrum antiviral agents against multiple enveloped viruses, by interrupting cellular Tsg101 interaction with maturing virus, thus blocking the budding process that releases particles from the cell.ImportanceThese results provide the basis for the development of drugs that target enveloped virus budding that can be used ultimately to control multiple virus infections in humans.
Host Response to Bacterial Pathogens and Non-Pathogens is Determined by Wnt5A Mediated Actin Organization
Authors: Jati Suborno , Sen Malini 
Published: May 2020

AbstractWnt5A signaling facilitates the killing of numerous bacterial pathogens but not non-pathogens. The basis of such distinction in killing remains unclear. Accordingly, we analyzed the influence of Wnt5A signaling on pathogenicE.coliK1 in relation to non-pathogenicE.coliK12-MG1655 andE.coliDH5α. We found that bacterial killing by macrophages is dictated by the effect of Wnt5A aided actin assembly on the incumbent bacteria. Actin assembly mediated by Wnt5A signaling antagonized the disruptive influence of internalizedE.coliK1 on cytoskeletal actin facilitating its eradication. However, internalizedE.coliK12-MG1655 andE.coliDH5α, which stabilize the actin cytoskleton remained unaffected by Wnt5A. Interestingly, actin assembly inhibitors altered bacterial phagosome compositions, supporting survival of K1, yet promoting killing of both K12-MG1655 and DH5α, in Wnt5A activated macrophages. Taken together, our study reveals the importance of Wnt5A signaling dependent assembly of cytoskeletal actin in determining the outcome of host response to bacterial pathogens and non-pathogens.
Type I interferons sensitise HIV-1-reactivating T-cells for NK cell-mediated elimination despite HDACi-imposed dysregulation of innate immunity
Authors: Prigann Julia , Postmus Dylan , Pietrobon Anna Julia , Wyler Emanuel , Jansen Jenny , Möller Lars , Fadejeva Jelizaveta , Steijaert Thijs H. , Fischer Cornelius , Koppe Uwe , Gunsenheimer-Bartmeyer Barbara , Meixenberger Karolin , Vitcetz Sarah N. , Sohn Madlen , Loyal Lucie , Thiel Andreas , Sauer Sascha , Sutter Kathrin , Dittmer Ulf , Laue Michael , Bannert Norbert , Landthaler Markus , Goffinet Christine 
Published: May 2020

ABSTRACTShock-and-kill is one of the most advanced, yet unrealized, concepts towards establishment of HIV-1 cure. Treatment with latency-reversing agents (LRAs), including histone deacetylase inhibitors (HDACis) exerting chromatin remodelling and gene expression reprogramming, combined with anti-retroviral therapy reactivates HIV-1 transcriptionin vitro,ex vivoandin vivo. However, HDACi treatment fails to significantly reduce the size of the viral reservoir in people living with HIV-1 (PLHIV). Here, by combining scRNA-seq and functional approaches, we characterised the HDACi treatment-imposed remodulation of CD4+ T-cells’ state and its consequences for HIV-1 latency reversal and the apparent resistance of HIV-1-reactivating cells to immune-mediated elimination. Exposure of CD4+T-cells from three aviremic PLHIV with clinically applicable concentrations of Panobinostat markedly reduced the expression of genes mediating T-cell activation and IFN-driven antiviral immunity in a largely CD4+T-cell subset-nonspecific manner, with exception of an PLHIV-specific exhausted CD4+T-cell subpopulation. Altered transcriptomic profiles were accompanied by large refractoriness to peptide and IL-2/PHA stimulation, and to exogenous type I interferon, that would otherwise induce T-cell activation and expression of a plethora of antiviral genes, respectively. Type I interferon, when added to Panobinostat during HIV-1 reactivation, was unable to counteract HDACi-mediated inhibition of IFN signalling and failed to interfere with HIV-1 reactivationper se. However, it imposed a pre-budding block and boosted surface levels of HIV-1 Env on reactivating cells. Co-treatment with type I IFNs, most prominently IFN-β and -α14, sensitised HIV-1-reactivating cells for killing by NK cells through antibody-dependent cytotoxicity. Together, our study provides proof-of-concept of the benefit of combining a potent LRA with immunostimulatory molecules, such as type I IFNs, to reduce the resistance of HIV-1-reactivating T-cells to immune-mediated elimination to improve current shock-and-kill strategies.
Circumpolar diversification of theIxodes uriaetick virome
Authors: Pettersson John H.-O. , Ellström Patrik , Ling Jiaxin , Nilsson Ingela , Bergström Sven , González-Acuña Daniel , Olsen Björn , Holmes Edward C. 
Published: May 2020

AbstractTicks (order: Ixodida) are a highly diverse and ecologically important group of ectoparasitic blood-feeding organisms. One such species, the seabird tick (Ixodes uriae), is widely distributed around the circumpolar regions of the northern and southern hemispheres. It has been suggested thatIx. uriaespread from the southern to the northern circumpolar region millions of years ago and has remained isolated in these regions ever since. Such a profound biographic subdivision provides a unique opportunity to determine whether viruses associated with ticks exhibit the same evolutionary patterns as their hosts. To test this, we collectedIx. uriaespecimens near a Gentoo penguin (Pygoscelis papua) colony at Neko harbour, Antarctica, and from migratory birds - the Razorbill (Alca torda) and the Common murre (Uria aalge) - on Bonden island, northern Sweden. Through meta-transcriptomic next- generation sequencing we identified 16 RNA viruses, seven of which were novel. Notably, we detected the same species, Ronne virus, and two closely related species, Bonden virus and Piguzov virus, in both hemispheres indicating that there have been at least two cross- circumpolar dispersal events. Similarly, we identified viruses discovered previously in other locations several decades ago, including Gadgets Gully virus, Taggert virus and Okhotskiy virus. By identifying the same or closely related viruses in geographically disjunct sampling locations we therefore provide evidence for virus dispersal within and between the circumpolar regions. In marked contrast, our phylogenetic analysis revealed no movement of theIx. uriaehosts between the same locations. Combined, these data suggest that migratory birds are responsible for the movement of viruses at both the local and global scales.Author summary/ImportanceAs host populations diverge, so may those microorganisms, including viruses, that are dependent on those hosts. To examine this key issue in host-microbial evolution we compared the co-phylogenies of the seabird tick,Ixodes uriae, and their RNA viruses sampled from the far northern and southern hemispheres. Despite the huge geographic distance between them, phylogeographic analysis reveals that the same viruses were found both within and between the northern and southern circumpolar regions, most likely reflecting transfer by virus-infected migratory birds. In contrast, genomic data suggested that theIx. uriaepopulations were phylogenetically distinct between the northern and southern hemispheres. This work emphasises the importance of migratory birds and ticks as vectors and sources of virus dispersal and introduction at both the local and global scales.
Importin α2 association with chromatin: Direct DNA binding via a novel DNA binding domain
Authors: Jibiki Kazuya , Kodama Takashi S. , Suenaga Atsushi , Kawase Yota , Shibazaki Noriko , Nomoto Shin , Nagasawa Seiya , Nagashima Misaki , Shimodan Shieri , Kikuchi Renan , Okayasu Mina , Takashita Ruka , Mehmood Rashid , Saitoh Noriko , Yoneda Yoshihiro , Akagi Ken-ichi , Yasuhara Noriko 
Published: May 2020

AbstractNuclear transport of proteins is important for facilitating appropriate nuclear functions. The proteins of the importin α family play key roles in nuclear transport as transport receptors for a huge number of nuclear proteins. Additionally, these proteins possess other functions, including chromatin association and gene regulation. However, these non-transport functions of importin α are not yet fully understood, especially their molecular-level mechanisms for functioning with chromatin and their consequences. Here, we report the novel molecular characteristics of importin α involving binding to diverse sequences in chromatin. We newly identified and characterized a DNA-binding domain—the Nucleic Acid Associating Trolley pole domain (NAAT domain)—in the N-terminal region of importin α within the conventional importin β binding (IBB) domain, which was shown to be necessary for nuclear transport of cargo proteins. We propose a ‘stroll and locate’ model to explain the association of importin α with chromatin. This is the first study to delineate the interaction between importin α and chromatin DNA via the NAAT domain, indicating the bifunctionality of the importin α N-terminal region for nuclear transport and chromatin association.
Primitive RNA-catalysis with guanine-rich oligonucleotide sequences – the case of a (GGC)3nonamer
Authors: Costanzo Giovanna , Cirigliano Angela , Pino Samanta , Giorgi Alessandra , Šedo Ondrej , Zdráhal Zbyněk , Stadlbauer Petr , Šponer Jiří , Šponer Judit E. , Di Mauro Ernesto 
Published: May 2020

AbstractA cornerstone of molecular evolution leading to the emergence of life on our planet is associated with appearance of the first catalytic RNA molecules. A question remains regarding the nature of the simplest catalytic centers that could mediate the chemistry needed for RNA-catalysis. In the current paper we provide a new example supporting our previously suggested model proposing that transiently formed open loop geometries could serve as temporary catalytic sites in the most ancient short oligonucleotides. In particular, using two independent detection techniques, PAGE and MALDI-ToF analysis, we show that prolonged thermal treatment of a 5’-phosphorylated (GGC)3sequence at weakly acidic or neutral pH in the presence of tris(hydroxymethyl)aminomethane, produces a species characterized by a (GGC)3G stoichiometry, which is compatible with the cleavage-terminal recombination chemistry suggested in our previous studies. Our new findings are complemented by microsecond-scale molecular dynamics simulations, showing that (GGC)3dimers readily sample transient potentially catalytic geometries compatible with the experimentally observed terminal recombination chemistry.
Just Add Data: Automated Predictive Modeling and BioSignature Discovery
Authors: Tsamardinos Ioannis , Charonyktakis Paulos , Lakiotaki Kleanthi , Borboudakis Giorgos , Zenklusen Jean Claude , Juhl Hartmut , Chatzaki Ekaterini , Lagani Vincenzo 
Published: May 2020

AbstractFully automated machine learning, statistical modelling, and artificial intelligence for predictive modeling is becoming a reality, giving rise to the field of Automated Machine Learning (AutoML). AutoML systems promise to democratize data analysis to non-experts, drastically increase productivity, improve replicability of the statistical analysis, facilitate the interpretation of results, and shield against common methodological analysis pitfalls. We present the basic ideas and principles of Just Add Data Bio (JADBIO), an AutoML technology applicable to the low-sample, high-dimensional omics data that arise in translational medicine and bioinformatics applications. In addition to predictive and diagnostic models ready for clinical use, JADBIO also returns the corresponding biosignatures, i.e., minimal-size subsets of biomarkers that are jointly predictive of the outcome of interest. A use-case on thymic epithelial tumors is presented, along with an extensive evaluation on 374 public biological datasets. Results show that long-standing challenges with overfitting and overestimation of complex non-linear machine learning pipelines on high-dimensional, low small sample data can be overcome.
Modeling cellular crosstalk and organotypic vasculature development with human iPSC-derived endothelial cells and cardiomyocytes
Authors: Helle Emmi , Ampuja Minna , Dainis Alexandra , Antola Laura , Temmes Elina , Mervaala Eero , Kivelä Riikka 
Published: May 2020

AbstractRationaleCell-cell interactions are crucial for the development and function of the organs. Endothelial cells act as essential regulators of tissue growth and regeneration. In the heart, endothelial cells engage in delicate bidirectional communication with cardiomyocytes. The mechanisms and mediators of this crosstalk are still poorly known. Furthermore, endothelial cells in vivo are exposed to blood flow and their phenotype is greatly affected by shear stress.ObjectiveWe aimed to elucidate how cardiomyocytes regulate the development of organotypic phenotype in endothelial cells. In addition, the effects of flow-induced shear stress on endothelial cell phenotype were studied.Methods and resultsHuman induced pluripotent stem cell (hiPSC) -derived cardiomyocytes and endothelial cells were grown either as a monoculture or as a coculture. hiPS-endothelial cells were exposed to flow using the Ibidi-pump system. Single-cell RNA sequencing was performed to define cell populations and to uncover the effects on their transcriptomic phenotypes. The hiPS-cardiomyocyte differentiation resulted in two distinct populations; atrial and ventricular. Coculture had a more pronounced effect on hiPS-endothelial cells compared to hiPS-cardiomyocytes. Coculture increased hiPS-endothelial cell expression of transcripts related to vascular development and maturation, cardiac development, and the expression of cardiac endothelial cell -specific genes. Exposure to flow significantly reprogrammed the hiPS-endothelial cell transcriptome, and surprisingly, promoted the appearance of both venous and arterial clusters.ConclusionsSingle-cell RNA sequencing revealed distinct atrial and ventricular cell populations in hiPS-cardiomyocytes, and arterial and venous-like cell populations in flow exposed hiPS-endothelial cells. hiPS-endothelial cells acquired cardiac endothelial cell identity in coculture. Our study demonstrated that hiPS-cardiomoycytes and hiPS-endothelial cells readily adapt to coculture and flow in a consistent and relevant manner, indicating that the methods used represent improved physiological cell culturing conditions that potentially are more relevant in disease modelling. In addition, novel cardiomyocyte-endothelial cell crosstalk mediators were revealed.
Examining sex-differentiated genetic effects across neuropsychiatric and behavioral traits
Authors: Martin Joanna , Khramtsova Ekaterina A. , Goleva Slavina B. , Blokland Gabriëlla A M. , Traglia Michela , Walters Raymond K. , Hübel Christopher , Coleman Jonathan R I. , Breen Gerome , Børglum Anders D. , Demontis Ditte , Grove Jakob , Werge Thomas , Bralten Janita , Bulik Cynthia M. , Lee Phil H. , Mathews Carol A. , Peterson Roseann E. , Winham Stacey J. , Wray Naomi , Edenberg Howard J. , Guo Wei , Yao Yin , Neale Benjamin M. , Faraone Stephen V. , Petryshen Tracey L. , Weiss Lauren A. , Duncan Laramie E. ,   Sex Differences Cross-Disorder Analysis Group of the Psychiatric Genomics Consortium, Goldstein Jill M. , Smoller Jordan W. , Stranger Barbara E. , Davis Lea K. 
Published: May 2020

AbstractBackgroundThe origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations across these traits, we tested for a sex-differentiated genetic architecture within and between traits.MethodsUsing genome-wide association study (GWAS) summary statistics for 20 neuropsychiatric and behavioral traits, we tested for differences in SNP-based heritability (h2) and genetic correlation (rg<1) between sexes. For each trait, we computed z-scores from sex-stratified GWAS regression coefficients and identified genes with sex-differentiated effects. We calculated Pearson correlation coefficients between z-scores for each trait pair, to assess whether specific pairs share variants with sex-differentiated effects. Finally, we tested for sex differences in between-trait genetic correlations.ResultsWith current sample sizes (and power), we found no significant, consistent sex differences in SNP-based h2. Between-sex, within-trait genetic correlations were consistently high, although significantly less than 1 for educational attainment and risk-taking behavior. We identified genome-wide significant genes with sex-differentiated effects for eight traits. Several trait pairs shared sex-differentiated effects. The top 0.1% of genes with sex-differentiated effects across traits overlapped with neuron- and synapse-related gene sets. Most between-trait genetic correlation estimates were similar across sex, with several exceptions (e.g. educational attainment & risk-taking behavior).ConclusionsSex differences in the common autosomal genetic architecture of neuropsychiatric and behavioral phenotypes are small and polygenic, requiring large sample sizes. Genes with sex-differentiated effects are enriched for neuron-related gene sets. This work motivates further investigation of genetic, as well as environmental, influences on sex differences.
Discovery and characterisation of an amidine-containing ribosomally-synthesised peptide that is widely distributed in nature
Authors: Russell Alicia H. , Vior Natalia M. , Hems Edward S. , Lacret Rodney , Truman Andrew W. 
Published: May 2020

ABSTRACTRibosomally synthesised and post-translationally modified peptides (RiPPs) are a structurally diverse class of natural product with a range of bioactivities. Genome mining for RiPP biosynthetic gene clusters (BGCs) is often hampered by poor detection of the short precursor peptides that are ultimately modified into the final molecule. Here, we utilise a previously described genome mining tool, RiPPER, to identify novel RiPP precursor peptides near YcaO-domain proteins, enzymes that catalyse various RiPP post-translational modifications including heterocyclisation and thioamidation. Using this dataset, we identified a novel, diverse and highly conserved family of RiPP BGCs spanning over 230 species of Actinobacteria and Firmicutes. A representative BGC fromStreptomyces albusJ1074 was characterised, leading to the discovery of streptamidine, a novel-amidine containing RiPP. This highlights the breadth of unexplored natural products with structurally rare features, even in model organisms.
Modeling disease progression in newly diagnosed type 2 diabetes
Authors: Hao Kun , Cao Yanguang 
Published: May 2020

ABSTRACTType 2 diabetes (T2DM) is a progressive disease, which is primarily characterized by a decline in β-cell function and worsening of insulin resistance. Unfortunately, most interventions (lifestyle, diet, and therapeutic agents) for T2DM only provide a transient restoration of β-cell function and the progression is inevitable once it starts. To understand the natural progression of T2DM, a mechanistic model was developed to quantitatively characterize the dynamic interactions among β-cell function, plasma fasting glucose (PFG), fasting insulin (FI), and the degree of insulin resistance, starting from an early stage of T2DM over up to 8 years. The model was validated using clinical data to optimize the disease parameters. The restoration and deterioration rates of β-cell function were both predicted as 84.5 %/year and 1.10 /year for early stages of T2DM. The model predicted a positive correlation between the initial level of β-cell function at diagnosis and its maximum restoration potential, underscoring the importance of early diagnosis and intervention. After the treatment, β-cell function could be temporarily restored within several months, which has a long-term benefit in glycemic control. The maximal tolerated PFG level that permits β-cell function restoration was predicted to be around 8.33 nM; and the temporal restoration of β-cell function would be unlikely at a PFG level above this threshold. The intrinsic deterioration rates of β-cell function and insulin resistance were both critical factors for long-term glycemic control. In conclusion, our model provides a quantitative analysis of the natural disease progression in T2DM and yields insights into factors that are critical for long-term glycemic control.