bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment- and population-specific genetic risk factors for anti-drug antibodies against interferon-beta
Authors: Andlauer Till F. M. , Link Jenny , Martin Dorothea , Ryner Malin , Hermanrud Christina , Grummel Verena , Auer Michael , Hegen Harald , Aly Lilian , Gasperi Christiane , Knier Benjamin , Müller-Myhsok Bertram , Hyldgaard Jensen Poul Erik , Sellebjerg Finn , Kockum Ingrid , Olsson Tomas , Pallardy Marc , Spindeldreher Sebastian , Deisenhammer Florian , Fogdell-Hahn Anna , Hemmer Bernhard ,   ABIRISK consortium
Published: May 2020

Background: Upon treatment with biopharmaceuticals, the immune system may produce anti-drug antibodies (ADA) that inhibit the therapy. Up to 40% of multiple sclerosis patients treated with interferon β (IFNβ) develop ADA, for which a genetic predisposition exists. Here, we present a genome-wide association study on ADA and predict the occurrence of antibodies in multiple sclerosis patients treated with different interferon β preparations.
Methods: We analyzed a large sample of 2,757 genotyped and imputed patients from two cohorts, split between a discovery and a replication dataset. Binding ADA (bADA) levels were measured by capture-ELISA, neutralizing ADA (nADA) titers using a bioassay. Genome-wide association analyses were conducted stratified by cohort and treatment preparation, followed by fixed-effects meta-analysis.
Results: Binding ADA levels and nADA titers were correlated and showed a significant heritability (47% and 50%, respectively). The risk factors differed strongly by treatment preparation: The top-associated and replicated variants for nADA presence were the HLA-associated variants rs77278603 in IFNβ-1a s.c.- (odds ratio (OR)=3.55 (95% confidence interval=2.81-4.48), p=2.1x10-26) and rs28366299 in IFNβ-1b s.c.-treated patients (OR=3.56 (2.69-4.72), p=6.6x10-19). The rs77278603-correlated HLA haplotype DR15-DQ6 conferred risk specifically for IFNβ-1a s.c. (OR=2.88 (2.29-3.61), p=7.4x10-20) while DR3-DQ2 was protective (OR=0.37 (0.27-0.52), p=3.7x10-09). The haplotype DR4-DQ3 was the major risk haplotype for IFNβ-1b s.c. (OR=7.35 (4.33-12.47), p=1.5x10-13). These haplotypes exhibit large population-specific frequency differences. In a cohort of IFNβ-1a s.c.-treated patients, prediction models for nADA reached an AUC of 0.91 (0.85-0.95), a sensitivity of 0.78, and a specificity of 0.90. Patients with the top 30% of genetic risk had, compared to patients in the bottom 30%, an OR of 73.9 (11.8 463.6, p=4.4x10-06) of developing nADA.
Conclusions: We identified several HLA-associated genetic risk factors for ADA against interferon β, which were specific for treatment preparations and population backgrounds. Genetic prediction models could robustly identify patients at risk for developing ADA and might be used for personalized therapy recommendations and stratified ADA screening in clinical practice. These analyses serve as a roadmap for genetic characterizations of ADA against other biopharmaceutical compounds.
Disruption of the CCL5/RANTES-CCR5 Pathway Restores Immune Homeostasis and Reduces Plasma Viral Load in Critical COVID-19
Authors: Patterson Bruce K. , Seethamraju Harish , Dhody Kush , Corley Michael J. , Kazempour Kazem , Lalezari Jay , Pang Alina P.S. , Sugai Christopher , Francisco Edgar B. , Pise Amruta , Rodrigues Hallison , Ryou Mathew , Wu Helen L. , Webb Gabriela M. , Park Byung S. , Kelly Scott , Pourhassan Nader , Lelic Alena , Kdouh Lama , Herrera Monica , Hall Eric , Aklin Enver , Ndhlovu Lishomwa C. , Sacha Jonah B.
Published: May 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is now pandemic with nearly three million cases reported to date1. Although the majority of COVID-19 patients experience only mild or moderate symptoms, a subset will progress to severe disease with pneumonia and acute respiratory distress syndrome (ARDS) requiring mechanical ventilation2. Emerging results indicate a dysregulated immune response characterized by runaway inflammation, including cytokine release syndrome (CRS), as the major driver of pathology in severe COVID-193,4. With no treatments currently approved for COVID-19, therapeutics to prevent or treat the excessive inflammation in severe disease caused by SARS-CoV-2 infection are urgently needed. Here, in 10 terminally-ill, critical COVID-19 patients we report profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell levels, and SARS-CoV-2 plasma viremia. Following compassionate care treatment with the CCR5 blocking antibody leronlimab, we observed complete CCR5 receptor occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. Consistent with reduction of plasma IL-6, single-cell RNA-sequencing revealed declines in transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes. These results demonstrate a novel approach to resolving unchecked inflammation, restoring immunologic deficiencies, and reducing SARS-CoV-2 plasma viral load via disruption of the CCL5-CCR5 axis, and support randomized clinical trials to assess clinical efficacy of leronlimab-mediated inhibition of CCR5 for COVID-19.
Characterizations of SARS-CoV-2 mutational profile, spike protein stability and viral transmission
Authors: Laha Sayantan , Chakraborty Joyeeta , Das Shantanab , Manna Soumen Kanti , Biswas Sampa , Chatterjee Raghunath
Published: May 2020

The recent pandemic of SARS-CoV-2 infection has affected more than 3.0 million people worldwide with more than 200 thousand reported deaths. The SARS-CoV-2 genome has a capability of gaining rapid mutations as the virus spreads. Whole genome sequencing data offers a wide range of opportunities to study the mutation dynamics. The advantage of increasing amount of whole genome sequence data of SARS-CoV-2 intrigued us to explore the mutation profile across the genome, to check the genome diversity and to investigate the implications of those mutations in protein stability and viral transmission. Four proteins, surface glycoprotein, nucleocapsid, ORF1ab and ORF8 showed frequent mutations, while envelop, membrane, ORF6 and ORF7a proteins showed conservation in terms of amino acid substitutions. Some of the mutations across different proteins showed co-occurrence, suggesting their functional cooperation in stability, transmission and adaptability. Combined analysis with the frequently mutated residues identified 20 viral variants, among which 12 specific combinations comprised more than 97% of the isolates considered for the analysis. Analysis of protein structure stability of surface glycoprotein mutants indicated viability of specific variants and are more prone to be temporally and spatially distributed across the globe. Similar empirical analysis of other proteins indicated existence of important functional implications of several variants. Analysis of co-occurred mutants indicated their structural and/or functional interaction among different SARS-COV-2 proteins. Identification of frequently mutated variants among COVID-19 patients might be useful for better clinical management, contact tracing and containment of the disease.
HIV Protease Inhibitor Nelfinavir Targets Human DDI2 and Potentiates Proteasome Inhibitor-based Chemotherapy
Authors: Gu Yuan , Wang Xin , Wang Yu , Li Jie , Yu Fa-Xing
Published: May 2020

Proteasome inhibitors (PIs) are currently used in the clinic to treat cancers such as multiple myeloma (MM). However, cancer cells often rapidly develop drug resistance towards PIs due to a compensatory mechanism mediated by nuclear factor erythroid 2 like 1 (NFE2L1) and aspartic protease DNA damage inducible 1 homolog 2 (DDI2). Following DDI2-mediated cleavage, NFE2L1 is able to induce transcription of virtually all proteasome subunit genes. Under normal condition, cleaved NFE2L1 is constantly degraded by proteasome, whereas in the presence of PIs, it accumulates and induces proteasome synthesis which in turn promotes the development of drug resistance towards PIs. Here, we report that Nelfinavir (NFV), an HIV protease inhibitor, can inhibit DDI2 activity directly. Inhibition of DDI2 by NFV effectively blocks NFE2L1 proteolysis and potentiates cytotoxicity of PIs in cancer cells. Recent clinical evidence indicated that NFV can effectively delay the refractory period of MM patients treated with PI-based therapy. Our finding hence provides a specific molecular mechanism for combinatorial therapy using NFV and PIs for treating MM and probably additional cancers.

Abstract Figure
1H MAS NMR of Donor Pancreatic Tissue is a Useful Predictor of Islet Viability Prior to Islet Isolation
Authors: Tanguay Lisa M.H. , Slupsky Carolyn M. , Toshiaki Toshiaki , Lix Bruce , Sykes Brian D. , Lakey Jonathan R.T.
Published: May 2020

The authors have withdrawn their manuscript because it was posted without the consent of all authors. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author
Rapid T cell receptor interaction grouping with ting
Authors: Mölder Felix , Stervbo Ulrik , Loyal Lucie , Bacher Petra , Babel Nina , Rahmann Sven
Published: May 2020

Motivation

Clustering of antigen-specific T cell receptor repertoire (TCRR) sequences is challenging. The recently published tool GLIPH aims to solve this problem. However, clustering large repertoires takes several days to weeks, making its use impractical in larger studies. In addition, the methodology used in GLIPH suffers from several shortcomings, including non-determinism, potential loss of significant antigen-specific sequences or inclusion of too many unspecific sequences.

Results

We present an algorithm for clustering TCRR sequences that scales efficiently to large repertoires. We clustered 26 real datasets with up to 62 000 unique CDR3βsequences using both GLIPH and an implementation of our method called ting. While GLIPH required multiple weeks, ting only needed about one hour for the same task. In addition, we found that in naïve repertoires, where no or very few antigen-specific CDR3 sequences or clusters should exist, our method indeed selects fewer sequences.

Availability

Our method has been implemented in Python as a tool called ting, using numpy and NetworkX. It is available on GitHub (https://github.com/FelixMoelder/ting) and on PyPI under the MIT license.

Contact

felix.moelder@uni-due.deorsven.rahmann@uni-due.de
Mechanistic insights into RNA binding and RNA-regulated RIG-I ubiquitination by TRIM25
Authors: Haubrich Kevin , Augsten Sandra , Álvarez Lucía , Huppertz Ina , Simon Bernd , Perez Kathryn , Masiewicz Pawel , Lethier Mathilde , Rittinger Katrin , Gabel Frank , Hentze Matthias W. , Cusack Stephen , Hennig Janosch
Published: May 2020

TRIM25 is a ubiquitin E3 ligase active in innate immunity and cell fate decisions. Mounting evidence suggests that TRIM25′s E3 ligase activity is regulated by RNAs. However, while mutations affecting RNA binding have been described, neither the precise RNA binding site has been identified nor which domains are involved. Here, we present biophysical evidence for the presence of RNA binding sites on both TRIM25 PRY/SPRY and coiled-coil domains, and map the binding site on the PRY/SPRY with residue resolution. Cooperative RNA-binding of both domains enhances their otherwise transient interaction in solution and increases the E3 ligase activity of TRIM25. We also show that TRIM25 not only binds RNA in mammalian cells but that interfering with RNA binding has an effect on cellular RIG-I ubiquitination.
A gradient of Wnt activity positions the neurosensory domains of the inner ear
Authors: Żak Magdalena , Plagnol Vincent , Daudet Nicolas
Published: May 2020

The auditory and vestibular organs of the inner ear and the neurons that innervate them originate from Sox2-positive and Notch-active neurosensory domains specified at early stages of otic development. Sox2 is initially present throughout the otic placode and otocyst, then it becomes progressively restricted to a ventro-medial domain. Using gain and loss-of-function approaches in the chicken otocyst, we show that these early changes in Sox2 expression are regulated in a dose-dependent manner by Wnt/beta-catenin signalling. Both high and very low levels of Wnt activity repress Sox2 and neurosensory competence. However, intermediate levels allow the maintenance of Sox2 expression and sensory organ formation. We propose that a dorso-ventral (high-to-low) gradient and wave of Wnt activity initiated at the dorsal rim of the otic placode progressively restricts Sox2 and Notch activity to the ventral half of the otocyst, thereby positioning the neurosensory competent domains in the inner ear.
Co-Phosphorylation Networks Reveal Subtype-Specific Signaling Modules in Breast Cancer
Authors: Ayati Marzieh , Chance Mark R , Koyutürk Mehmet
Published: May 2020

Motivation

Protein 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.

Results

We 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 implementation

CoPPNetis 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

In 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.

Importance

These 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

Wnt5A 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

Shock-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

Ticks (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/Importance

As 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

Nuclear 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

A 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

Fully 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

Rationale

Cell-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.

Objective

We 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 results

Human 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.

Conclusions

Single-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

Background

The 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.

Methods

Using 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.

Results

With 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).

Conclusions

Sex 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

Ribosomally 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

Type 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.
Endophyte inoculation enhancesUlmus minorresistance to Dutch elm disease
Authors: Martínez-Arias C , Sobrino-Plata J , Ormeño-Moncalvillo S , Gil L , Rodríguez-Calcerrada J , Martín JA
Published: May 2020

Certain fungal endophytes are known to improve plant resistance to biotic stresses in forest trees. In this study, three stem fungal endophytes belonging to classes Cystobasidiomycetes, Eurotiomycetes and Dothideomycetes were selected from 210 isolates for their potential as enhancers ofUlmus minorresistance toOphiostoma novo-ulmi. We evaluated phenotypic traits of these endophytes that could be beneficial for inhibitingO. novo-ulmiin the host plant. Underin vitroconditions, the Dothideomycetous isolate YCB36 strongly inhibitedO. novo-ulmigrowth, released antipathogenic VOCs, chitinases and siderophores, and overlapped with the pathogen in nutrient utilization patterns. These functional traits could explain the 40% reduction in leaf wilting due toO. novo-ulmiin elm trees pre-inoculated with this endophyte.Ulmus minortrees inoculated with this endophyte showed increased leaf stomatal conductance and higher concentrations of flavonoids and total phenolic compounds in xylem tissues, suggesting induction of defence metabolism.
The Notch Ligand Jagged1 is Required for the Formation, Maintenance, and Survival of Hensen Cells in the Mouse Cochlea
Authors: Chrysostomou Elena , Zhou Luyi , Darcy Yuanzhao L. , Graves Kaley A. , Doetzlhofer Angelika , Cox Brandon C.
Published: May 2020

During cochlear development, the Notch ligand JAGGED 1 (JAG1) plays an important role in the specification of the prosensory region, which gives rise to sound-sensing hair cells and neighboring supporting cells (SCs). While JAG1’s expression is maintained in SCs through adulthood, the function of JAG1 in SC development is unknown. Here, we demonstrate that JAG1 is essential for the formation and maintenance of Hensen cells (HeCs), a highly specialized SC-subtype located at the edge of the auditory epithelium. Deletion ofJag1at the onset of differentiation, at stage E14.5, disrupted HeC formation. Similar loss of HeCs was observed whenJag1was deleted at P0/P1 and fate-mapping analysis revealed that in the absence ofJag1some HeCs die, but others convert into neighboring Claudius cells. In support of a role for JAG1 in cell survival, genes involved in mitochondrial function and protein synthesis were downregulated in P0 cochlea lackingJag1.
The contribution of stimulating multiple body parts simultaneously to the illusion of owning an entire artificial body
Authors: O’Kane Sophie H. , Ehrsson H. Henrik
Published: May 2020

The full-body ownership illusion exploits multisensory perception to induce a feeling of ownership for an entire artificial body. Whilst previous research has shown that the synchronous visuotactile stimulation of a single body part is sufficient for illusory ownership over the whole body, the effect of combining multisensory stimulation across multiple body parts remains unknown. Therefore, 48 healthy adults participated in conditions of a full-body ownership illusion involving synchronous or asynchronous visuotactile stimulation to one, two or three body parts simultaneously (2 x 3 design). We developed a novel questionnaire to isolate the sense of ownership of five specific body parts (left leg, right leg, left arm, right arm, and trunk) from the full-body ownership experience and sought not only to test for greater (part and whole) body ownership in synchronous versus asynchronous stimulation, but also, potentially varying degrees of illusion intensity related to the number of body parts stimulated. As expected, illusory full-body ownership and all five body-part ownership ratings were significantly higher following synchronous stimulation (all p values ≤.01). Since non-stimulated body parts also received significantly higher ownership ratings following synchronous stimulation, the results are consistent with an illusion engaging the entire body. We further noted that ownership ratings for the right body parts (often stimulated) were significantly higher than ownership ratings for the left body parts (never stimulated). Regarding explicit feelings of full-body ownership, subjective ratings were not significantly enhanced by increasing the number of synchronously stimulated body parts (synchronicity x number stimulated interaction; p.099). Instead, median ratings indicated a moderate affirmation (+1) of full-body illusory sensation for all three synchronous conditions; a finding mirrored by full-body illusion onset time. The results support the notion that feelings of full-body ownership are mediated by a generalisation from stimulated part(s)-to-whole, supported by processes related to multisensory body perception.
Disentangling listening effort and memory load beyond behavioural evidence: Pupillary response to listening effort during a concurrent memory task
Authors: Zhang Yue , Lehmann Alexandre , Deroche Mickael
Published: May 2020

Recent research has demonstrated that pupillometry is a robust measure for quantifying listening effort. However, pupillary responses in listening situations where multiple cognitive functions are engaged and sustained over a period of time remain hard to interpret. This limits our conceptualisation and understanding of listening effort in realistic situations, because rarely in everyday life are people challenged by one task at a time. Therefore, the purpose of this experiment was to reveal the dynamics of listening effort in a sustained listening condition using a word repeat and recall task.

Words were presented in quiet and speech-shaped noise at different signal-to-noise ratios (SNR). Participants were presented with lists of 10 words, and required to repeat each word after its presentation. At the end of the list, participants either recalled as many words as possible or moved on to the next list. Simultaneously, their pupil dilation was recorded throughout the whole experiment.

When only word repeating was required, peak pupil dilation (PPD) was bigger in 0dB versus other conditions; whereas when recall was required, PPD showed no difference among SNR levels and PPD in 0dB was smaller than repeat-only condition. Baseline pupil diameter and PPD followed different growth patterns across the 10 serial positions in conditions requiring recall: baseline pupil diameter built up progressively and plateaued in the later positions (but shot up at the onset of recall, i.e. the end of the list); PPD decreased at a pace quicker than in repeat-only condition.

The current findings concur with the recent literature in showing that additional cognitive load during a speech intelligibility task could disturb the well-established relation between pupillary response and listening effort. Both the magnitude and temporal pattern of task-evoked pupillary response differ greatly in complex listening conditions, urging for more listening effort studies in complex and realistic listening situations.
DECODING SECOND ORDER ISOMORPHISMS IN THE BRAIN: The case of colors and letters
Authors: José Hanson Stephen , Caglar Leyla Roskan , Hanson Catherine
Published: May 2020

We introduce a new method for decoding neural data from fMRI. It is based on two assumptions, first that neural representation is distributed over networks of neurons embeded in voxel noise and second that the stimuli can be decoded as learned relations from sets of categorical stimuli. We illustrate these principles with two types of stimuli, color (wavelength) and letters (visual shape), both of which have early visual system response, but at the same time must be learned within a given function or category (color contrast, alphabet). Key to the decoding method is reducing the stimulus cross-correlation by a matched noise voxel sample by normalizing the stimulus voxel matrix thus unmasking a highly discriminative neural profile per stimulus. Projection of this new voxel space (ROI) to a smaller set of dimensions (with e.g., non-metric Multidimensional scaling), the relational information takes a unique geometric form revealing functional relationships between sets of stimuli, defined by R. Shepard, assecond-order isomorphisms (SOI). In the case of colors the SOI appears as a nearly equally spaced set of wavelengths arranged in a color wheel, with a gap between the “purples” and “reds” (consistent with the gap in the original Ekman’s color set). In the case of letters, a cluster space resulted from the decorrelated voxel neural profiles, which matched the phrase structure of the mnemonic used for more than 100 years to teach children the alphabet (across multiple languages),The Alphabet Song.
Transcription of intragenic CpG islands influences spatiotemporal host gene pre-mRNA processing
Authors: Amante Samuele M , Montibus Bertille , Cowley Michael , Barkas Nikolaos , Setiadi Jessica , Saadeh Heba , Giemza Joanna , Castillo Stephania Contreras , Fleischanderl Karin , Schulz Reiner , Oakey Rebecca J
Published: May 2020

Alternative splicing (AS) and alternative polyadenylation (APA) generate diverse transcripts in mammalian genomes during development and differentiation. Epigenetic factors such as trimethylation of histone H3 lysine 36 (H3K36me3) and DNA methylation play a role in generating transcriptome diversity. Intragenic CpG islands (iCGIs) and their corresponding host genes exhibit dynamic epigenetic and gene expression patterns during development and between different tissues. We hypothesise that iCGI-associated H3K36me3, DNA methylation and transcription can influence host gene AS and/or APA. We investigate H3K36me3 and find that this histone mark is not a major regulator of AS or APA in our model system. Genomewide, we identify over 4000 host genes that harbour an iCGI in the mammalian genome, including both previously annotated and novel iCGI/host gene pairs. The transcriptional activity of these iCGIs is tissue- and developmental stage-specific and, for the first time, we demonstrate that the premature termination of host gene transcripts upstream of iCGIs is closely correlated with the level of iCGI transcription in a DNA-methylation independent manner. These studies suggest that iCGI transcription, rather than H3K36me3 or DNA methylation, interfere with host gene transcription and pre-mRNA processing genomewide and contributes to the spatiotemporal diversification of both the transcriptome and proteome.