bluuebunny/crossref_metadata_2025_split huggingface dataset:
RASSF effectors couple diverse RAS subfamily GTPases to the Hippo pathway
Authors: Thillaivillalan Dhanaraman , Singh Swati , Killoran Ryan C. , Singh Anamika , Xu Xingjian , Shifman Julia , Smith Matthew J. 
Published: February 2020

AbstractActivated RAS GTPases signal by directly binding effector proteins. Effectors have a folded RAS association (RA) domain that binds exclusively to GTP-loaded RAS, but the specificity of most RA domains for >150 RAS superfamily GTPases is unknown. Ten RAS-association domain family (RASSF) proteins comprise the largest group of effectors, proposed to couple RAS to the pro-apoptotic Hippo pathway. We show that RASSF1-6 complex with Hippo kinase, while RASSF7-10 are a separate family related to p53-regulatory ASPP effectors. Only RASSF5 directly binds activated HRAS and KRAS. Structural modelling reveals that expansion of RASSFs in vertebrates included amino acid substitutions that alter their GTPase binding specificity. We demonstrate that the tumour suppressor RASSF1A complexes with the GTPases GEM, REM1, REM2 and the enigmatic RASL12. Interplay between RASSFs and RAS GTPases can drastically restrict YAP1 nuclear localization. Thus, these simple scaffolds can link activation of diverse RAS proteins to Hippo or p53 regulation.
Protective anti-prion antibodies in human immunoglobulin repertoires
Authors: Senatore Assunta , Frontzek Karl , Emmenegger Marc , Chincisan Andra , Losa Marco , Reimann Regina , Horny Geraldine , Guo Jingjing , Fels Sylvie , Sorce Silvia , Zhu Caihong , George Nathalie , Ewert Stefan , Pietzonka Thomas , Hornemann Simone , Aguzzi Adriano 
Published: February 2020

AbstractPrion immunotherapy may hold great potential, but antibodies against certain PrP epitopes can be neurotoxic. Here we identified >6000 PrP-binding antibodies in a synthetic human Fab phage display library, 49 of which we characterized in detail. Antibodies directed against the flexible tail of PrP conferred neuroprotection against infectious prions. We then mined published repertoires of circulating B cells from healthy humans and found antibodies similar to the protective phage-derived antibodies. When expressed recombinantly, these antibodies exhibited anti-PrP reactivity. Furthermore, we surveyed 48’718 samples from 37’894 hospital patients for the presence of anti-PrP IgGs, and found 21 high-titer individuals. The clinical files of these individuals did not reveal any enrichment of specific pathologies, suggesting that anti-PrP autoimmunity is innocuous. The existence of protective anti-prion antibodies in unbiased human immunological repertoires, combined with the reported lack of such antibodies in carriers of disease-associatedPRNPmutations, suggests a link to the low incidence of spontaneous prion diseases in human populations.
Short-term heritable variation overwhelms two hundred generations of mutational variance for metabolic traits inCaenorhabditis elegans
Authors: Baer Charles F. , Hahn Dan , Johnson Lindsay M , Smith Olivia J 
Published: February 2020

ABSTRACTMetabolic disorders have a large heritable component, and have increased over the past few generations. Genome-wide association studies of metabolic traits typically find a substantial unexplained fraction of total heritability, suggesting an important role of spontaneous mutation. An alternative explanation is that epigenetic effects contribute significantly to the heritable variation. Here we report a study designed to quantify the cumulative effects of spontaneous mutation on adenosine metabolism in the nematodeCaenorhabditis elegans, including both the activity and concentration of two metabolic enzymes and the standing pools of their associated metabolites. The only prior studies on the effects of mutation on metabolic enzyme activity, inDrosophila melanogaster, found that total enzyme activity presents a mutational target similar to that of morphological and life-history traits. However, those studies were not designed to account for short-term heritable effects. We find that the short-term heritable variance for most traits is of similar magnitude as the variance among MA lines. This result suggests that the potential heritable effects of epigenetic variation in metabolic disease warrant additional scrutiny.
Multitask learning for Transformers with application to large-scale single-cell transcriptomes
Authors: Pang Minxing , Tegnér Jesper 
Published: February 2020

AbstractRecent progress in machine learning provides competitive methods for bioinformatics in many traditional topics, such as transcriptomes sequence and single-cell analysis. However, discovering biomedical correlation of cells that are present across large-scale data sets remains challenging. Our attention-based neural network module with 300 million parameters is able to capture biological knowledge in a data-driven way. The module contains high-quality embedding, taxonomy analysis and similarity measurement. We tested the model on Mouse Brain Atlas, which consists of 160,000 cells and 25,000 genes. Our module obtained some interesting findings that have been verified by biologists and got better performance when benchmarked against autoencoder and principal components analysis.
GENVISAGE: Rapid Identification of Discriminative and Explainable Feature Pairs for Genomic Analysis
Authors: Huang Silu , Blatti Charles , Sinha Saurabh , Parameswaran Aditya 
Published: February 2020

AbstractMotivationA common but critical task in genomic data analysis is finding features thatseparateand thereby help explain differences between two classes of biological objects, e.g., genes that explain the differences between healthy and diseased patients. As lower-cost, high-throughput experimental methods greatly increase the number of samples that are assayed as objects for analysis, computational methods are needed to quickly provide insights into high-dimensional datasets with tens of thousands of objects and features.ResultsWe develop an interactive exploration tool called Genvisagethat rapidly discovers the most discriminative feature pairs that best separate two classes in a dataset, and displays the corresponding visualizations. Since quickly finding top feature pairs is computationally challenging, especially when the numbers of objects and features are large, we propose a suite of optimizations to make Genvisagemore responsive and demonstrate that our optimizations lead to a400Xspeedup over competitive baselines for multiple biological data sets. With this speedup, Genvisageenables the exploration of more large-scale datasets and alternate hypotheses in an interactive and interpretable fashion. We apply Genvisageto uncover pairs of genes whose transcriptomic responses significantly discriminate treatments of several chemotherapy drugs.AvailabilityFree webserver athttp://genvisage.knoweng.org:443/with source code athttps://github.com/KnowEnG/Genvisage
Impact of Cancer-Associated Mutations in Hsh155/SF3b1 HEAT Repeats 9-12 on pre-mRNA Splicing inSaccharomyces cerevisiae
Authors: Kaur Harpreet , Groubert Brent , Paulson Joshua C. , McMillan Sarah , Hoskins Aaron A. 
Published: February 2020

AbstractMutations in the splicing machinery have been implicated in a number of human diseases. Most notably, the U2 small nuclear ribonucleoprotein (snRNP) component SF3b1 has been found to be frequently mutated in blood cancers such as myelodysplastic syndromes (MDS). SF3b1 is a highly conserved HEAT repeat (HR)-containing protein and most of these blood cancer mutations cluster in a hot spot located in HR4-8. Recently, a second mutational hotspot has been identified in SF3b1 located in HR9-12 and is associated with acute myeloid leukemias, bladder urothelial carcinomas, and uterine corpus endometrial carcinomas. The consequences of these mutations on SF3b1 functions during splicing have not yet been tested. We incorporated the corresponding mutations into the yeast homolog of SF3b1 and tested their impact on splicing. We find that all of these HR9-12 mutations can support splicing in yeast, and this suggests that none of them are loss of function alleles in humans. The Hsh155V502Fmutation alters splicing of several pre-mRNA reporters containing weak branch sites as well as a genetic interaction with Prp2 and physical interactions with Prp5 and Prp3. The ability of a single allele of Hsh155 to perturb interactions with multiple factors functioning at different stages of the splicing reaction suggests that some SF3b1-mutant disease phenotypes may have a complex origin on the spliceosome.
RIG-I and PKR, but not stress granules, mediate the pro-inflammatory response to Yellow fever virus
Authors: Beauclair Guillaume , Streicher Felix , Bruni Daniela , Gracias Ségolène , Bourgeau Salomé , Sinigaglia Laura , Fujita Takashi , Meurs Eliane F. , Tangy Frédéric , Jouvenet Nolwenn 
Published: February 2020

AbstractYellow fever virus (YFV) is an RNA virus primarily targeting the liver. Severe YF cases are responsible for hemorrhagic fever, plausibly precipitated by excessive pro-inflammatory cytokine response. Pathogen recognition receptors (PRRs), such as the cytoplasmic RIG-I-like receptors (RLRs), and the viral RNA sensor PKR are known to initiate a pro-inflammatory response upon recognition of viral genomes. Here, we sought to reveal the main determinants responsible for the acute cytokine expression occurring in human hepatocytes following YFV infection. Using a RIG-I-defective human hepatoma cell line, we found that RIG-I largely contributes to cytokine secretion upon YFV infection. In infected RIG-I-proficient hepatoma cells, RIG-I was localized in stress granules. These granules are large aggregates of stalled translation preinitiation complexes known to concentrate RLRs and PKR, and are so far recognized as hubs orchestrating RNA virus sensing. Using PKR-deficient hepatoma cells, we found that PKR contributes to both stress granule formation and cytokine induction upon YFV infection. However, stress granules disruption did not affect the cytokine response to YFV infection, as assessed by siRNA-knockdown-mediated inhibition of stress granule assembly. Finally, no viral RNA was detected in stress granules using a fluorescencein situhybridization approach coupled with immunofluorescence. Our findings suggest that both RIG-I and PKR mediate pro-inflammatory cytokine induction in YFV-infected hepatocytes, in a stress granule-independent manner. Therefore, by showing the uncoupling of the early cytokine response from the stress granules formation, our model challenges the current view by which stress granules are required for the mounting of the acute antiviral response.ImportanceYellow fever is a mosquito-borne acute hemorrhagic disease caused by yellow fever virus (YFV). The mechanisms responsible for its pathogenesis remain largely unknown, although increased inflammation has been linked to worsened outcome. YFV targets the liver, where it primarily infects hepatocytes. We found that two RNA-sensing proteins, RIG-I and PKR, participate in the induction of pro-inflammatory mediators in human hepatocytes infected with YFV. We show that YFV infection promotes the formation of cytoplasmic structures, termed stress granules, in a PKR-, but not RIG-I-dependent manner. Whilst stress granules were previously postulated to be essential platforms for immune activation, we found that they are not required for pro-inflammatory mediators’ production upon YFV infection. Collectively, our work uncovered molecular events triggered by the replication of YFV, which could prove instrumental in clarifying the pathogenesis of the disease, with possible repercussions on disease management.
The versatility of Ascorbate Peroxidase-aided mapping uncovers insights of the nuclear lamina interactions and function
Authors: Tran Joseph R. , Paulson Danielle I. , Moresco James J. , Adam Stephen A. , Yates John R. , Goldman Robert D. , Zheng Yixian 
Published: February 2020

AbstractThe nuclear lamina (NL) is a proteinaceous network found beneath the inner nuclear membrane. The NL is linked to a number of dynamic cellular activities including chromatin organization, transcription and RNA/protein trafficking through nuclear pores. Our understanding of the NL has been hindered in part by the general insolubility and low extractability of proteins from this region. This has spurred the development of proximity ligation methods that label proteins and/or DNA near the NL for systematic identification (Bar et al., 2018; Chen et al., 2018b; Guelen et al., 2008; Roux et al., 2012). To simplify labeling and improve temporal resolution, we fused APEX2 (Hung et al., 2014; Lam et al., 2015) to the nuclear lamina protein lamin-B1 to map proteins, RNA and DNA associated with the NL. We show that APEX2 labeling of the NL is robust and requires as little as 20 seconds. In addition to identifying the NL proteome, this method revealed NL-proximal RNA species that were largely spliced. These NL-proximal RNAs show a bias toward long 3’ UTRs, suggesting an RNA-regulatory role of the NL. This is further supported by the finding of a bias toward longer 3’ UTRs in genes deregulated in lamin-null cells. Interestingly, these RNAs share a sequence motif in their 3’ UTRs. Finally, we demonstrate that the APEX2 method can reliably map lamina-associated domains (LADs) at different stages of the cell cycle, revealing a variability of short LADs regions enriched for histone lysine 27 trimethylation (H3K27me3). Thus the APEX2 method report here is a useful addition to the molecular toolbox for the study of the NL and permits the identification of proteome, transcriptome, and genome elements associated with this nuclear substructure.
Direct Imaging of Liquid Domains in Membranes by Cryo Electron Tomography
Authors: Cornell Caitlin E. , Mileant Alexander , Thakkar Niket , Lee Kelly K. , Keller Sarah L. 
Published: February 2020

ABSTRACTImages of micron-scale domains in lipid bilayers have provided the gold standard of model-free evidence to understand the domains’ shapes, sizes, and distributions. Corresponding techniques to directly and quantitatively assess smaller (nanoscale and submicron) liquid domains have been lacking, leading to an inability to answer key questions. For example, researchers commonly seek to correlate activities of membrane proteins with attributes of the domains in which they reside; doing so hinges on identification and characterization of membrane domains. Although some features of membrane domains can be probed by indirect methods, these methods are often constrained by the limitation that data must be analyzed in the context of models that require multiple assumptions or parameters. Here, we address this challenge by developing and testing two new methods of identifying submicron domains in biomimetic membranes. Both methods leverage cryo-electron tomograms of ternary membranes under native solution conditions. The first method is optimized for probe-free applications: domains are directly distinguished from the surrounding membrane by their thickness. This technique measures area fractions of domains with quantitative accuracy, in excellent agreement with known phase diagrams. The second method is optimized for applications in which a single label is deployed for imaging membranes by both high-resolution cryo-electron tomography and diffraction-limited optical microscopy. For this method, we test a panel of probes, find that a trimeric mCherry label performs best, and specify criteria for developing future high-performance, dual-use probes. These developments have led to the first direct and quantitative imaging of submicron membrane domains under native conditions.SIGNIFICANCE STATEMENTFluorescence micrographs that capture the sizes, shapes, and distributions of liquid domains in model membranes have provided high standards of evidence to prove (and disprove) theories of how micron-scale domains form and grow. Corresponding theories about smaller domains have remained untested, partly because experimental methods of identifying submicron domains in vesicles under native solvent conditions have not been available. Here we introduce two such methods. Both leverage cryo-electron tomography to observe membrane features far smaller than the diffraction limit of light. The first method is probe-free and identifies differences in thicknesses between liquid domains and their surrounding membranes. The second method identifies membrane regions labeled by an electron-dense, fluorescent protein, which enables direct comparison of fluorescence micrographs with cryo-electron tomograms.
Increasing social engagement among college students with autism
Authors: Fairchild Lyndsay A. , Powell Margaret B. , Gadke Daniel L. , Spencer Jordan C. , Stratton Kasee K. 
Published: February 2020

Purpose
Many university-based services for individuals with autism spectrum disorder (ASD) have incorporated peer mentorship programs; however, the research on the success of these programs to increase social engagement is extremely limited. This study aims to examine the effectiveness of a peer mentor program, both alone and combined with an incentive program, on increasing the social engagement of college students with ASD. Additionally, the perceptions of college students with ASD were also examined to determine potential barriers to participate in these social events.

Design/methodology/approach
A component analysis was used to determine what intervention component or combination of components, was most effective in increasing the social engagement among college students with ASD. The number of students during each component was totaled and averaged across the number of social events held during that phase. A survey regarding barriers to social engagement was also provided.

Findings
Results suggest that both the peer mentor program alone, as well as the peer mentor program in conjunction with an incentive program, were effective at increasing students’ attendance at weekly supervised social events. Results from the survey regarding barriers to social engagement revealed that the majority of students reported difficulties managing time to fit social events into their schedule.

Originality/value
To the knowledge, the use of peer-mentoring programs combined with an incentive program on increasing social engagement has not yet been investigated. Further, perceptions of the use of these programs by college students with ASD is relatively limited.
The impact of public relations on visibility of Croatian non-profits
Authors: Polić Mirela , Cesarec Salopek Nataša 
Published: February 2020

Purpose
The purpose of this paper is to understand and show how public relations contributed to enhancing the visibility of Croatian non-profit organization Foundation “Croatia for Children” and its activities within its stakeholders, as well as how public relations contributed to the mobilization of target publics in Foundation’s activities.

Design/methodology/approach
Using a single case study approach, data were collected over a 12-month period. Quantitative and qualitative media research was applied in order to compare visibility of Foundation in the period before and after the strategic communication campaign.

Findings
Strategic communication campaign enhanced the visibility of Foundation “Croatia for Children” in national and local Croatian media and positioned it as the primary instance for children without an adequate parental care and children in need. However, local media devoted more attention comparing to the national media. All children wishes (1,000) were fulfilled by mobilizing the target publics.

Research limitations/implications
The results derived from this case study cannot be generalized since they are based on a single case in one country.

Practical implications
This study can serve as a starting point for another research about the role and importance that public relations have in enhancing the visibility of non-profit organizations.

Originality/value
The results of this study point to the role and importance public relations have in the non-profit sector in order to proactively communicate with all stakeholders in society.
The effect of colonial legacies on Africa’s inward FDI: the case of UK FDI in Ghana
Authors: Osei Collins , Omar Maktoba , Joosub Tasneem Suliman 
Published: February 2020

PurposeThe purpose of this paper is to examine the role colonial ties play in attracting foreign direct investment (FDI) to Ghana, several years after the official end of colonisation in the African continent. Colonisation left behind legacies of institutional framework, social ties and remnants of companies of colonial masters, which could potentially offer contemporary businesses from home countries the benefits of country of origin agglomeration.Design/methodology/approachThis paper uses sequential explanatory mixed research design through 101 questionnaires and 8 interviews from the UK companies with FDI in Ghana. This approached enabled the initial quantitative results to be explored further through the qualitative data.FindingsColonial ties have limited influence on contemporary flow of FDI to Ghana, in spite of the institutional legacies between former colonisers and colonies. Majority of UK companies are influenced by agglomeration opportunities in general rather than country of origin agglomeration. However, country of origin agglomeration remains important to over a third of the companies surveyed.Research limitations/implicationsThe sample was taken from the non-extractive industry in Ghana, and caution must be applied in generalising the findings. However, some universal issues concerning agglomeration and institutions are discussed.Originality/valueAlthough there has been some research on colonial history and its impact on FDI in Africa, existing knowledge on bilateral relations is rather limited. Unlike previous studies, this research provides depth by examining colonial influence on FDI between two countries, using two key concepts: country of origin agglomeration and institutions. It provides UK companies with contemporary views to consider when exploring FDI opportunities in Ghana, particularly in relation to the effects of the colonial history. It also provides investment promotion agencies with empirical results on the importance of various forms of agglomeration and institutions for FDI attraction.
Employee value proposition: an analysis of organizational factors – the way to enhance value perception
Authors: Rounak Sujata , Misra Rajnish Kumar 
Published: February 2020

Purpose
The purpose of this paper is to draw attention to the organizational factors that can impact the perception of value proposition as offered by organizations. It aims to highlight the importance of Perceived Organizational Support (POS), Organization’s Perceived Identity (OPI) and Exchange Quality in enhancing the value perception among employees.

Design/methodology/approach
This study is based on a review of the literature and offers a conceptual analysis to explain the impact of POS, OPI and exchange quality on the employee’s perception of value proposition.

Findings
POS, OPI and exchange quality can act as social exchange elements and can co-create value for internal customers thereby enhancing value perception. They act as the stimuli for the employees which make them realize the benefits that they are offered by the organization.

Research limitations/implications
This is a conceptual paper hence based on literature review of relevant papers.

Practical implications
This study has major implications for understanding the factors that can improve the overall workplace experience of employees and can make the organization one of the best places to work. This will, in turn, enhance employee retention and can be a major strategy of talent management.

Originality/value
The paper provides a novel approach to show the enhancement in value perception by these three factors i.e. POS, OPI and exchange quality with the help of relevant literature.