bluuebunny/crossref_metadata_2025_split huggingface dataset:
Possible co-option of a VEGF-driven tubulogenesis program for biomineralization in echinoderms
Authors: Morgulis Miri , Gildor Tsvia , Roopin Modi , Sher Noa , Malik Assaf , Lalzar Maya , Dines Monica , Khalaily Lama , de-Leon Smadar Ben-Tabou 
Published: February 2019

AbstractBiomineralization is the process in which living organisms use minerals to form hard structures that protect and support them. Biomineralization is believed to have evolved rapidly and independently in different phyla utilizing existing components used for other purposes. The mechanistic understanding of the regulatory networks that drive biomineralization and their evolution is far from clear. The sea urchin skeletogenesis is an excellent model system for studying both gene regulation and mineral uptake and deposition. The sea urchin calcite spicules are formed within a tubular cavity generated by the skeletogenic cells under the control the vascular endothelial growth factor (VEGF) signaling. The VEGF pathway controls tubulogenesis and vascularization across metazoans while its regulation of biomineralization was only observed in echinoderms. Despite the critical role of VEGF signaling in sea urchin spiculogenesis, the downstream program it activates was largely unknown. Here we study the cellular and molecular machinery activated by the VEGF pathway during sea urchin spiculogenesis and reveal multiple parallels to the regulation of tubulogenesis during vertebrate vascularization. Human VEGF rescues sea urchin VEGF knock-down; VEGF-dependent vesicle deposition plays a significant role in both systems and sea urchin VEGF signaling activates hundreds of genes including biomineralization and vascularization genes. Five upstream transcription factors and three signaling genes active in spiculogenesis are homologous to vertebrate factors that regulate vascularization. Overall, our findings suggest that sea urchin spiculogenesis and vertebrate vascularization diverged from a common ancestral tubulogenesis program, broadly adapted for vascularization and specifically co-opted for biomineralization in the echinoderm phylum.Significance statementThe sea urchin calcite spicules and vertebrate blood vessels are quite distinct in their function, yet both have a tubular structure and are controlled by the vascular endothelial growth factor (VEGF) pathway. Here we study the downstream program by which VEGF pathway drives sea urchin spiculogenesis and find remarkable similarities to the control of vertebrate vascularization. The similarities are observed both in the upstream gene regulatory network, in the downstream effector genes and the cellular processes that VEGF signaling controls at the site of the calcite spicule formation. We speculate that sea urchin spiculogenesis and vertebrate vascularization diverged from a common ancestral tubulogenesis program that was co-opted for biomineralization in the echinoderm phylum.
Notch signalling mediates secondary senescence
Authors: Teo Yee Voan , Rattanavirotkul Nattaphong , Salzano Angela , Quintanilla Andrea , Tarrats Nuria , Kiourtis Christos , Mueller Miryam , Green Anthony R. , Adams Peter D. , Acosta Juan-Carlos , Bird Thomas G. , Kirschner Kristina , Neretti Nicola , Chandra Tamir 
Published: February 2019

AbstractOncogene induced senescence (OIS) is a tumour suppressive response to oncogene activation that can be transmitted to neighbouring cells through secreted factors of the senescence associated secretory phenotype (SASP). Using single-cell transcriptomics we observed two distinct endpoints, a primary marked by Ras and a secondary by Notch. We find that secondary senescence in vitro and in vivo requires Notch, rather than SASP alone as previously thought. Currently, primary and secondary senescent cells are not thought of as functionally distinct endpoints. A blunted SASP response and the induction of fibrillar collagens in secondary senescence compared to OIS point towards a functional diversification.One Sentence SummaryNotch signalling is an essential driver of secondary senescence with primary and secondary senescence being distinct molecular endpoints.
Immune-informed mucin hydrogels evade fibrotic foreign body response in vivo
Authors: Yan Hongji , Seignez Cédric , Hjorth Morgan , Winkeljann Benjamin , Lieleg Oliver , Phillipson Mia , Crouzier Thomas 
Published: February 2019

AbstractThe immune-mediated foreign body response to biomaterial implants can trigger the formation of insulating fibrotic capsules that can compromise implant function. To address this challenge, we leverage the intrinsic bioactivity of the mucin biopolymer, a heavily glycosylated protein that forms the protective mucus gel covering mucosal epithelia. By using a bioorthogonal inverse electron demand Diels-Alder reaction, we crosslink mucins into implantable hydrogels. We show that mucin hydrogels (Muc-gels) modulate the immune response driving biomaterial-induced fibrosis. Muc-gels did not elicit fibrosis 21 days after implantation in the peritoneal cavity of C57Bl/6 mice, whereas medical-grade alginate hydrogels (Alg-gels) were covered by fibrous tissues. Further, Muc-gels dampened the recruitment of innate and adaptive immune cells to the gel and triggered a pattern of very mild activation marked by a noticeably low expression of the fibrosis-stimulating TGF-β1 cytokine. With this advance in mucin materials, we provide an essential tool to better understand mucin bioactivities and to initiate the development of new mucin-based and mucin-inspired ‘immune-informed’ materials for implantable devices subject to fibrotic encapsulation.
Raman Spectroscopic Study of the Influence of Oxytocin and Uvariodendron anisatum Verdeck (Annonaceae) Freeze-dried Extracts on Diet Induced Obesity in Sprague Dawley Rats
Authors: Birech Zephania , Sehmi Prabjot K. , Mwangi Peter W. , Nyaga Nelly M. 
Published: February 2019

AbstractObesity is a condition affecting many people in the world. Obese people have increased risks of developing chronic metabolic diseases such as type II diabetes, hypertension, cancer among others. Early and rapid diagnosis of the condition together with effective treatment is therefore necessary. This work investigated, first, Raman spectroscopic similarities between oxytocin and a freeze-dried extract of a local herbal plant exhibiting oxytocin-like properties called Uvariodendron anisatum Verdeck (Annonaceae) (UAV). Secondly, whether Raman spectroscopy could be used for comparative studies of the influence of oxytocin and UAV on diet induced obesity in Sprague Dawley (SD) rat models. We also sought for obesity or metabolic syndrome biomarker Raman spectral bands. Both oxytocin and extract samples together with blood extracted from the rats were excited using a 785 nm laser with conductive silver paste smeared glass slides as Raman sample substrates. It was found that Raman spectral profiles of oxytocin solution and UAV freeze dried extract’s powder were identical with a cosine similarity value of 0.95 implying presence of similar Raman active molecules. The prominent peaks were those assigned to disulphide S-S stretching mode at 508 cm−1 and to tyrosine at 645 cm−1, 846 cm−1 and 1617 cm−1. Raman spectra of blood from oxytocin- and UAV-treated rats displayed similar profiles which were different from those of obese and non-obese (normal controls) animals. A prominent peak in spectra of treated rats centred at 401 cm−1 could be used as oxytocin biomarker band in blood. Comparison of average intensity trend of fructose bands at around 638 cm−1 and 812 cm−1 between prepared fructose solution and blood of treated rats, revealed elevated levels of fructose in blood of rats intraperitoneally injected oxytocin and UAV extracts. The result implied upregulation of fructose in oxytocin and UAV treated animals. Principal component analysis (PCA) showed that the Raman spectral profiles from blood of obese rats were different from those of non-obese rats. It also showed that spectra from oxytocin treated and UAV treated rat’s blood were similar indicating identical influence. The study shows the potential of Raman spectroscopy as tool for quick obesity (metabolic syndrome) screening with intensity of Raman bands associated with fructose acting as biomarkers. The same bands can also be used in comparative efficacy studies of anti-obesity drugs. Further studies are needed to validate these Raman spectroscopic results since, to the best of our knowledge, this was the first such investigation regarding comparison of UAV and conventional oxytocin together with their influence on obese SD rats. Weather human subjects exhibits similar results are also not known.
Metabolic Reprogramming: Short-term Western Diet Exposure Induces Sustained Changes in Plasma Metabolites
Authors: Misra Biswapriya B. , Upadhayay Ram P. , Mattern Vicki , Parks John S. , Cox Laura A. , Comuzzie Anthony G. , Olivier Michael 
Published: February 2019

AbstractDietary patterns are well known to contribute to the metabolic syndrome and related disorders. We evaluated the impact of a short-term Westernized diet (WD) exposure on systemic plasma metabolomic changes in a cohort of adult male baboons. In this pilot study, five male baboons (n=5) raised and maintained on a standard monkey chow diet (high complex carbohydrates, low fat) were exposed to a challenge WD (high in saturated fats and simple carbohydrates) for 7 weeks (49 d), followed by a 57-day washout period on monkey chow (106 d). In addition to monitoring clinical measures, we used a comprehensive two-dimensional gas chromatography-time-of-flight mass spectrometry (2D GC-ToF-MS) platform to assess the metabolomic changes in plasma at three time points. Twenty-three metabolites were changed in response to the WD (49 d), but the response across the animals was highly variable. All animals presented a very different metabolic profile than at baseline (0 d), and the washout period resulted in a relatively homogenous metabolic state across all animals. A short-term exposure to a WD led to long-term changes in the metabolic profile, suggesting a “reset” of the metabolic program.
A CyclinB2-Cas9 fusion promotes the homology-directed repair of double-strand breaks
Authors: Vicente Manuel M. , Mendes Afonso , Cruz Margarida , Vicente José R. , Barreto Vasco M. 
Published: February 2019

ABSTRACTThe discovery of clustered regularly interspaced palindromic repeats (CRISPR), a defense system against viruses found in bacteria, launched a new era in gene targeting. The key feature of this technique is the guiding of the endonuclease Cas9 by single guide RNAs (sgRNA) to specific sequences, where a DNA lesion is introduced to trigger DNA repair. The CRISPR/Cas9 system may be extremely relevant for gene therapy, but the technique needs improvement to become a safe and fully effective tool. The Cas9-induced double-strand break (DSB) is repaired by one of two pathways, the error-prone Non-homologous end joining (NHEJ) or the high-fidelity Homology Direct Repair (HDR). Shifting the repair of the DSB to HDR is challenging, given the efficiency of NHEJ. Here we describe an engineered protein approach to increase knock-in efficiency by promoting the relative increase in Cas9 activity in G2, the phase of the cell cycle where HDR is more active. Cas9 was fused to the degradation domain of proteins known to be degraded in G1. The activity of two chimeric proteins, Geminin-Cas9 and CyclinB2-Cas9, is demonstrated, as well as their cell-cycle-dependent degradation. The chimeras shifted the repair of the DSBs to the HDR repair pathway compared to the commonly used Cas9. The application of cell cycle specific degradation tags could pave the way for more efficient and secure gene editing applications of the CRISPR/Cas9 system.
Metagenomic dynamics in Olea europaea after root damage and Verticillium dahliae infection
Authors: Martí Jose Manuel , Arias Luis F. , Díaz Wladimiro , Arnau Vicente , Rodriguez-Franco Antonio , Garay Carlos P. 
Published: February 2019

AbstractThe olive tree is of particular economic interest in the Mediterranean basin. Researchers have conducted several studies on one of the most devastating disorders affecting this tree, the Verticillium wilt of olive, which causes significant economic damage in numerous areas of this crop. We have analyzed the temporal metagenomic samples of a transcriptomic study in Olea europaea roots and leaves after root-damage and after a root Verticillium dahliae infection (Jimenez-Ruiz et al. 2017). Our results indicate that this infection, although led by Verticillium, is driven not by a single species but by a polymicrobial community, including their natural endophytes, which acts as a consortium in the attack to the host plant. This community includes both biotrophic and necrotrophic organisms that alternate and live together during the infection. Our results not only describe how the microbial community progresses along these processes, but also explain the high complexity of these systems, that in turn, could justify at least in part the occasional changes and disparity found at the time of classifying the kind of parasitism of a determined organism.
Genome-wide estimates of heritability and genetic correlations in Essential Tremor
Authors: Diez-Fairen Monica , Bandres-Ciga Sara , Houle Gabrielle , Nalls Mike A. , Girard Simon L. , Dion Patrick A. , Blauwendraat Cornelis , Singleton Andrew B. , Rouleau Guy A. , Pastor Pau 
Published: February 2019

ABSTRACTDespite considerable efforts to identify disease-causing and risk factors contributing to essential tremor (ET), no comprehensive assessment of heritable risk has been performed to date. We use GREML-LDMS to estimate narrow-sense heritability due to additive effects (h2) and GREMLd to calculate non-additive heritability due to dominance variance (δ2) using data from 1,748 ET cases and 5,302 controls. We evaluate heritability per 10Mb segments across the genome and assess the impact of Parkinson’s disease (PD) misdiagnosis on heritability estimates. We apply genetic risk score (GRS) from PD and restless legs syndrome (RLS) to explore its contribution to ET risk and further assess genetic correlations with 832 traits by Linkage disequilibrium score regression. Our results show for the first time that ET is a highly heritable condition (h2=0.755, s.e=0.075) in which additive common variability plays a prominent role. In contrast, dominance variance shows insignificant effect on the overall estimates. Heritability split by 10Mb regions revealed increased estimates at chromosomes 6 and 21 suggesting that these may contain causative risk variants influencing susceptibility to ET. The proportion of genetic variance due to PD misdiagnosed cases was estimated to be 5.33%. PD and RLS GRS were not significantly predictive of ET case-control status demonstrating that despite overlapping symptomatology, ET does not seem to share genetic etiologies with PD or RLS. Our study suggests that most of ET genetic component is yet to be discovered and future GWAS will reveal additional risk factors that will improve our understanding of this disabling disorder.
Structural features underlying the activity of benzimidazole derivatives that target phosphopeptide recognition by the tandem BRCT domain of the BRCA1 protein
Authors: Kurdekar Vadiraj , Giridharan Saranya , Subbarao Jasti , Nijaguna Mamatha B. , Periasamy Jayaprakash , Boggaram Sanjana , Bharatham Kavitha , Potluri Vijay , Shivange Amol V. , Sadasivam Gayathri , Padigaru Muralidhara , Venkitaraman Ashok R. 
Published: February 2019

AbstractThe tandem BRCT (tBRCT) domains of BRCA1 engage pSer-containing motifs in target proteins to propagate intracellular signals initiated by DNA damage, thereby controlling cell cycle arrest and DNA repair. Recently, we identified Bractoppin, a benzimidazole that represents a first selective small molecule inhibitor of phosphopeptide recognition by the BRCA1 tBRCT domains, which selectively interrupts BRCA1-mediated cellular responses evoked by DNA damage. Here, we combine structure-guided chemical elaboration, protein mutagenesis and cellular assays to define the structural features that underlie the biochemical and cellular activities of Bractoppin. Bractoppin fails to bind mutant forms of BRCA1 tBRCT bearing single residue substitutions that alter K1702, a key residue mediating phosphopeptide recognition (K1702A), or alter hydrophobic residues (F1662R or L1701K) that adjoin the pSer-recognition site. However, mutation of BRCA1 tBRCT residue M1775R, which engages the Phe residue in the consensus phosphopeptide motif pSer-X-X-Phe, does not affect Bractoppin binding. Collectively, these findings confirm a binding mode for Bractoppin that blocks the phosphopeptide-binding site via structural features distinct from the substrate phosphopeptide. We explored these structural features through structure-guided chemical elaboration of Bractoppin, synthesizing analogs bearing modifications on the left and right hand side (LHS/RHS) of Bractoppin’s benzimidazole ring. Characterization of these analogs in biochemical assay reveal structural features underlying potency. Analogs where the LHS phenyl is replaced by cyanomethyl (2091) and 4-methoxyphenoxypropyl (2113) conceptualized from structure-guided strategies like GIST and dimer interface analysis expose the role of phenyl and isopropyl as critical hydrophobic anchors. Two Bractoppin analogs, 2088 and 2103 were effective in abrogating BRCA1 foci formation and inhibiting G2 arrest induced by irradiation of cells. Collectively, our findings reveal structural features underlying the biochemical and cellular activity of a novel benzimidazole inhibitor of phosphopeptide recognition by the BRCA1 tBRCT domain, providing fresh insights to guide the development of inhibitors that target the protein-protein interactions of this previously undrugged family of protein domains.
Newly Discovered migratory corridor and foraging ground for Atlantic green turtles, Chelonia mydas, nesting on Bioko Island, Equatorial Guinea
Authors: Mettler Emily , Clyde-Brockway Chelsea E. , Honarvar Shaya , Paladino Frank V. 
Published: February 2019

AbstractThis study is the first to use satellite telemetry to track post-nesting movements of endangered green turtles (Chelonia mydas) in the Gulf of Guinea. Satellite transmitters were attached in 2018 to six Atlantic green turtles nesting on Bioko Island, Equatorial Guinea, to track their post-nesting movements and locate their foraging grounds. Track lengths of 20-198 days were analyzed, for a total of 536 movement days for the six turtles. Migratory pathways and foraging grounds were identified by applying a switching state space model to locational data, which provides daily position estimates to identify shifts between migrating and foraging behavior. Turtles exhibited a combination of coastal and oceanic migrations pathways that ranged from 957 km to 1,131 km. Of the six turtles, five completed their migration and maintained residency at the same foraging ground near the coastal waters of Accra, Ghana until transmission was lost. These five resident turtles inhabit heavily fished and polluted waters and are vulnerable to a variety of anthropogenic threats. The identification of these foraging grounds highlights the importance of these coastal waters for the protection of the endangered Atlantic green turtle.
Impact of e-servicescapes on student engagement: mediating impact of experience quality
Authors: Dassanayake Hansani Chathurika , Senevirathne Asanka 
Published: February 2019

Purpose
The purpose of this paper is to investigate the impact of design of e-servicescapes on student engagement in distance education (DE), and examine whether this impact is mediated by student experience quality.

Design/methodology/approach
Quantitative research approach based on cross-sectional survey design was adapted where data were collected using a structured questionnaire. Sample consisted of 252 undergraduates registered in the DE platform in Sri Lanka and was drawn using a simple random sampling technique. Collected data were analysed using the structural equation modelling.

Findings
Data analysis revealed that there is a direct significant impact of e-servicescapes on student engagement while this impact is partially mediated by student experience quality in the Sri Lankan context. Meantime, the social presence feature of e-servicescapes has the highest impact on student engagement.

Practical implications
Findings of the study provide an empirically validated model to boost up the student engagement and significantly contribute to the designing of the e-servicescapes of the DE institutes in order to offer a superior service to a wide array of stakeholders.

Originality/value
Even though e-servicescapes have been recognised as a driver of customer behaviour, the concept is fairly unexplored in the educational context. Due to its practical applicability in the DE context, this study contributes to the existing knowledge by presenting a novel conceptual model developed based on multiple theories to identify its impact on student behaviour.
Conversation skills training for people with autism through virtual reality: using responsible research and innovation approach
Authors: Politis Yurgos , Sung Connie , Goodman Lizbeth , Leahy Michael 
Published: February 2019

Purpose
Users’ role in co-designing products has changed: from influencing outcomes to influencing development/design; from standardizing to customising products/outcomes; from participating to engaging designers/developers. Although this participatory design (PD) approach makes users’ role more prominent it has been under-utilised for the technological development of products for people with neurodevelopmental disabilities (NDD). The purpose of this paper is to present a responsible research and innovation example, in conversation skills training for people with autism, using virtual reality (VR).

Design/methodology/approach
The PD approach was adopted during the iterative development of the virtual world and training materials. Multiple baseline design was utilised consisting of three participants on the mild/moderate end of the autism spectrum. Participants joined 15–16 sessions over four phases of structured conversations, delivered both face-to-face and virtually.

Findings
The feedback sessions revealed that the participants felt VR has the potential in providing training for people with autism spectrum disorders. Moreover, they thought delivering the training in three formats could enhance their learning, since PowerPoints, videos and chatbot would represent teaching, showing and practicing, respectively.

Social implications
PD promotes a “one-size-fits-one approach”, cultivating agile, inclusive, responsive design approaches for people with NDDs, so that outcome meets their needs and preferences, while VR training allows for a wider implementation, benefiting a wider range of learners.

Originality/value
The RRI approach increases the inclusion of people with disabilities in the decision-making process through dialogue with “experts”, making their role more visible, fostering an ethical and sustainable innovation process, leading to more desirable outcomes.