bluuebunny/crossref_metadata_2025_split huggingface dataset:
The landscape of interactions between cancer polygenic risk scores and somatic alterations in cancer cells
Authors: Porta-Pardo Eduard , Sayaman Rosalyn , Ziv Elad , Valencia Alfonso 
Published: September 2020

AbstractOver the last 15 years we have identified hundreds of inherited variants that increase the risk of developing cancer. Polygenic risk scores (PRS) summarize the genetic risk of each individual by accounting for the unique combination of risk alleles in their genome. So far, most studies of PRS in cancer have focused on their predictive value: i.e. to what extent the PRS can predict which individuals will develop a particular cancer type. In parallel, for most cancers, we have identified several subtypes based on their somatic molecular properties. However, little is known about the relationship between the somatic molecular subtypes of cancer and PRS and it is possible that PRS preferentially predict specific cancer subtypes. Since cancer subtypes can have very different outcomes, treatment options and molecular vulnerabilities, answering this question is very important to understand the consequences that widespread PRS use would have in which tumors are detected early.Here we used data from The Cancer Genome Atlas (TCGA) to study the correlation between PRS for different forms of cancer and the landscape of somatic alterations in the tumors developed by each patient. We first validated the predictive power of 8 different PRS in TCGA and describe how PRS for some cancer types are associated with specific molecular subtypes or somatic cancer driver events. Our results highlight important questions that could improve the predictive power of PRS and that need to be answered before their widespread clinical implementation.
SOCS-1 inhibition of type I interferon limitsStaphylococcus aureusskin host defense
Authors: Klopfenstein Nathan , Brandt Stephanie , Castellanos Sydney , Serezani C. Henrique 
Published: September 2020

AbstractThe innate immune response to methicillin-resistantStaphylococcus aureus(MRSA) skin infection culminates in forming an abscess that prevents the bacterial spread and tissue damage. Pathogen recognition receptors (PRRs) dictate the balance between microbial control and tissue damage. Therefore, intracellular brakes are of fundamental importance to tune the appropriate host defense while preventing injury. The intracellular inhibitor suppressor of cytokine signaling 1 (SOCS-1); is a classic JAK/STAT inhibitor that prevents PRR responses by influencing the expression and actions of PRR adaptors and downstream effectors. Whether SOCS-1 is a molecular component of skin host defense remains to be determined. Here, we hypothesized that SOCS-1 decreases type I interferon production and IFNAR-mediated antimicrobial effector functions of the inflammatory response during MRSA skin infection. Our data show that MRSA skin infection enhances SOCS-1 expression, and both SOCS-1 inhibitor peptide treated and myeloid-specific SOCS-1 deficient mice display decreased lesion size, bacterial loads, and increased abscess thickness when compared to wild-type mice treated or not with scrambled peptide control. SOCS-1 deletion/inhibition increases phagocytosis and bacterial killing, dependent on nitric oxide release. SOCS-1 inhibition also increases antimicrobial effector function correlated with type I and type II interferon levelsin vivo. IFNAR deletion and antibody blockage abolished the beneficial effects of SOCS-1 inhibitionin vivo. Notably, we unveiled that hyperglycemia triggers aberrant SOCS-1 expression that correlates with decreased overall IFN signatures in the skin. SOCS-1 inhibition restores skin host defense in highly susceptible hyperglycemic mice. Overall, these data demonstrate a role for type I interferons in enhancing microbial clearance and host defense during MRSA skin infection.
ColwelliaandMarinobactermetapangenomes reveal species-specific responses to oil and dispersant exposure in deepsea microbial communities
Authors: Peña-Montenegro Tito David , Kleindienst Sara , Allen Andrew E. , Eren A. Murat , McCrow John P. , Sánchez-Calderón Juan David , Arnold Jonathan , Joye Samantha B. 
Published: September 2020

AbstractOver 7 million liters of Corexit EC9500A and EC9527A were applied to the Gulf of Mexico in response to the Deepwater Horizon oil spill. The impacts of dispersants remain under debate and negative, positive, and inconclusive impacts have been reported. Here, metatrancriptomics was applied in the context of metapangenomes to microcosms that simulated environmental conditions comparable to the hydrocarbon-rich 1,100 m deep plume. Within this microcosm study, negative effects of dispersants on microbial hydrocarbon degradation were previously reported based on activity measurements and geochemical data. Transcriptional enrichment ofColwellia, a potential dispersant degrader, followed variable time-dependent trajectories due to interactions between oil, dispersants, and nutrients. TheColwelliametapangenome captured a mixture of environmental responses linked to theColwellia psychrerythraea34H genome and to the genomes of other members of theColwelliagenus. The activation of genes involved in lipid degradation, nitrogen metabolism, and membrane composition under oil or nutrient availability, suggested an opportunistic growth strategy forColwellia. In contrast, transcripts ofMarinobacter, a natural hydrocarbon degrader, increased only in oil treatments.Marinobactertranscripts largely recruited to the accessory metapangenome ofMarinobactersp. C18, the closest genomic reference. A complex response involving carbon and lipid metabolism, chemotaxis and a type IV secretion system suggested active energy-dependent processes inMarinobacter. These findings highlight chemistry-dependent responses in the metabolism of key hydrocarbon-degrading bacteria and underscore that dispersant-driven selection could temper the ability of the community to respond to hydrocarbon injection.
Regulation of RUVBL1-RUVBL2 AAA-ATPases by the nonsense-mediated mRNA decay factor DHX34, as evidenced by Cryo-EM
Authors: López-Perrote Andrés , Hug Nele , González-Corpas Ana , Rodríguez Carlos F. , Serna Marina , García-Martín Carmen , Boskovic Jasminka , Fernandez-Leiro Rafael , Caceres Javier F. , Llorca Oscar 
Published: September 2020

AbstractNonsense-mediated mRNA decay (NMD) is a surveillance pathway that degrades aberrant mRNAs and also regulates the expression of a wide range of physiological transcripts. RUVBL1 and RUVBL2 AAA-ATPases form an hetero-hexameric ring that is part of several macromolecular complexes such as INO80, SWR1 and R2TP. Interestingly, RUVBL1-RUVBL2 ATPase activity is required for NMD activation by an unknown mechanism. Here, we show that DHX34, an RNA helicase regulating NMD initiation, directly interacts with RUVBL1-RUVBL2in vitroand in cells. Cryo-EM reveals that DHX34 induces extensive changes in the N-termini of every RUVBL2 subunit in the complex, stabilizing a conformation that does not bind nucleotide and thereby down-regulates ATP hydrolysis of the complex. Using ATPase-deficient mutants, we find that DHX34 acts exclusively on the RUVBL2 subunits. We propose a model, where DHX34 acts to couple RUVBL1-RUVBL2 ATPase activity to the assembly of factors required to initiate the NMD response.
Preclinical characterization of mobocertinib highlights the putative therapeutic window of this novel EGFR inhibitor to EGFR exon 20 insertion mutations
Authors: Vasconcelos Pedro E. N. S. , Kobayashi Ikei S. , Kobayashi Susumu S. , Costa Daniel B. 
Published: September 2020

AbstractBackgroundEpidermal growth factor receptor (EGFR) exon 20 insertion mutations account for 10% of all EGFR mutations and are mostly insensitive to approved EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Novel EGFR-TKIs have been developed or repurposed for these mutants. A limited number of preclinical studies have detailed these EGFR-TKIs. We sought to use commercially available mobocertinib (TAK-788) to characterize the preclinical therapeutic window of this EGFR-TKI against EGFR mutations and to probe possible on-target mechanisms of resistance (EGFR-C797S).MethodsWe used models of EGFR mutations to probe representative 1st, 2nd, 3rdgeneration, and in-development EGFR exon 20-active (poziotinib, mobocertinib) TKIs. We also introduced EGFR-C797S to these models to identify mechanisms of resistance.ResultsCells driven by the most common EGFR exon 20 insertion mutations (A767_V769dupASV, D770_N771insSVD, H773_V774insH and others) were inhibited by in-development EGFR TKIs at doses below those affecting EGFR-wildtype; albeit more common EGFR mutations (exon 19 deletions and L858R) were inhibited more readily by mobocertinib and poziotinib. Mobocertinib was able to inhibit phosphorylation of EGFR in multiple preclinical models. The presence of EGFR-C797S led to >200-fold resistance in proliferation assays probing mobocertinib and osimertinib. Review of clinical studies of mobocertinib disclosed responses that could be lasting.ConclusionsThis is one of the initial reports to characterize the novel EGFR TKI mobocertinib and highlights its broad activity against EGFR mutants plus the therapeutic window to EGFR exon 20 insertion mutations; as well as EGFR-C797S as a possible mechanism of resistance. Further clinical development of mobocertinib merits continuation.
TRAIL signalling promotes entosis in colorectal cancer
Authors: Bozkurt Emir , Düssmann Heiko , Salvucci Manuela , Cavanagh Brenton L. , Van Schaeybroeck Sandra , Longley Daniel B. , Martin Seamus J. , Prehn Jochen H. M. 
Published: September 2020

AbstractEntosis is a form of non-phagocytic cell-in-cell (CIC) interaction where a living cell enters into another. Tumours show evidence of entosis, however factors controlling entosis remain to be elucidated. Here we find that the death receptor ligand TRAIL is a potent activator of entosis in colon cancer cells. CLEM/3D confocal microscopy analysis revealed ultrastructural features of entosis and subsequent entotic cell death of inner cells upon TRAIL treatment. Induction of entosis and apoptosis by TRAIL were mutually exclusive events but both required the presence of caspase-8.Bax/Bakdouble knock-out or caspase inhibition altered the fate of inner cells from entotic cell death to survival and escape. Analysis of colorectal cancer tumours showed a significant association between expression levels of TRAIL and CICs. Notably, the presence of CICs in the invasive front regions of colorectal tumours was significantly correlated with adverse patient prognosis.
An evolutionarily diverged mitochondrial protein controls biofilm growth and virulence inCandida albicans
Authors: Mamouei Zeinab , Singh Shakti , Lemire Bernard , Gu Yiyou , Alqarihi Abdullah , Nabeela Sunna , Li Dongmei , Ibrahim Ashraf , Uppuluri Priya 
Published: September 2020

AbstractA forward genetic screening approach identified orf19.2500, as a gene controllingCandida albicansbiofilm dispersal and biofilm detachment. Three-dimensional (3-D) protein modeling and bioinformatics revealed that orf19.2500 is a conserved mitochondrial protein, structurally similar to, but functionally diverged from, the squalene/phytoene synthases family. TheC. albicansorf19.2500 is distinguished by three evolutionarily acquired stretches of amino acid inserts, absent from all other eukaryotes except a small number of ascomycete fungi. Biochemical assays showed that orf19.2500 is required for the assembly and activity of theNADHubiquinone oxidoreductase Complex I of the respiratory electron transport chain, and was thereby namedNDU1.NDU1is essential for respiration and growth on alternative carbon sources, important for immune evasion, required for virulence in a mouse model of hematogenously disseminated candidiasis, and for potentiating resistance to antifungal drugs. Our study is the first report on a protein that sets theCandida-like fungi phylogenetically apart from all other eukaryotes, based solely on evolutionary “gain” of new amino acid inserts that are also the functional hub of the protein.
Effects of technology lock-in on enterprise innovation performance
Authors: Zhao Li , Sun Jianxin , Zhang Ling , He Pengfei , Yi Qiulu 
Published: September 2020

PurposeThis study explores the effects of different types of technology lock-in on enterprise innovation performance. On this basis, the authors aim to provide technological innovation suggestions for the long-term development of Chinese enterprises.Design/methodology/approachA total of 211 high-tech enterprises in China were taken as the research sample. Data were collected through questionnaire surveys and secondhand data. Linear and nonlinear regression models were used to test the hypotheses.FindingsDifferent types of technology lock-in had different effects on enterprise innovation performance. Initiative lock-in and passive lock-in showed an inverted U-shaped relationship with innovation performance. Economies of scale were positively correlated with innovation performance, while self-lock-in was negatively correlated with it.Practical implicationsThis research can help enterprises reconceptualize technology lock-in. It can also help enterprises in different stages of development carry out targeted technological innovation and management strategies.Originality/valueThis research enriches our understanding of technology lock-in. By breaking with previous conceptualizations of a simple linear relationship between technology lock-in and innovation performance, this study proposes and confirms different technology lock-in has different relationships with enterprise innovation performance. This study is important for enterprises to reassess their technology lock-in state and carry out targeted technological innovation strategies. This research enriches the theory of path dependence and its combination with other theories. And this study also reveals the current research on technology lock-in is insufficient.
International entrepreneurship education for pre-service teachers: a longitudinal study
Authors: Arruti Arantza , Paños-Castro Jessica 
Published: September 2020

PurposeThe purpose of this paper is to explore whether participating in an entrepreneurship education programme with short-term international placements can help pre-service teachers to identifying the characteristics of entrepreneurial competence from a wide definition of entrepreneurship (Lackéus, 2015) rather than from a business centred definition, to be developed by entrepreneur teachers.Design/methodology/approachA three-year longitudinal qualitative study was carried out. In-depth interviews were conducted using open-ended questions with 17 pre-service teachers from the University of Deusto (Spain). They were participating in a European project with short-term international placements at five different European higher education institutions.FindingsThere is no consensual definition of the term entrepreneurship, which varies depending on the context. Entrepreneurship could be considered to be both a mindset and a lifestyle. The characteristics of entrepreneurs that were mentioned the most included: being creative, team players, open-minded, innovative, passionate, motivated, hard-working and risk-takers; being able to overcome challenges; having initiative; being proactive, organised and persevering; having leadership skills, communication skills, the ability to adapt; having a positive attitude and, being decision-makers. Short-term placements contribute to personal development, improved foreign language competence, increased awareness and understanding of other cultures, and acquiring entrepreneurship competence.Originality/valueResearch on the characteristics of teacherpreneurs is still in its early stages. The vast majority of studies focus on entrepreneurs and teachers of entrepreneurship education programmes aimed at those who wish to start up new businesses. This study contributes to a better understanding of the term entrepreneurship, to identifying the current characteristics of teacherpreneurs, and to outline certain variables that could be considered during pre-service teachers training plans. It also proposes further research into in-service teacherpreneur education.
Build back better concepts for resilient recovery: a case study of India’s 2018 flood recovery
Authors: Neeraj Shankar , Mannakkara Sandeeka , Wilkinson Suzanne 
Published: September 2020

Purpose
This paper aims to understand the recovery process after the 2018 floods in Kerala, India, and it determines whether the recovery efforts were aligned with Build Back Better (BBB) concepts.

Design/methodology/approach
A qualitative approach was adopted to collect the data from the officials of Government and NGOs involved in Kerala recovery. The participants were interviewed on the challenges faced during the recovery process and the actions taken by them to overcome it.

Findings
The study identified that the Kerala Government was proactive at making the community resilient from future disasters by – encouraging owner-driven reconstruction among flood-affected households; supporting locals to rejuvenate their business; and by creating a local-level recovery authority. Further, this paper identifies the areas that Kerala was lacking in terms of BBB and where resilience-based plans and actions are needed for the future.

Research limitations/implications
The participants were employees of Government and NGOs at a state level as they were the primary decision-makers to implement any recovery actions. Researchers believe that the authorities at district and village level could have had a different perspective towards implementing the recovery actions.

Practical implications
The best practices presented in this paper for effective BBB will assist the government to build/improve resilience in the community.

Originality/value
The implementation of BBB concepts in the areas of disaster risk reduction, community recovery and effective implementation was never studied extensively. The research provides valuable information on what extent Kerala’s post-disaster recovery and reconstruction activities were in-line with BBB practices.
Coopetition and sales performance: evidence from non-mainstream sporting clubs
Authors: Crick James M. , Crick Dave 
Published: September 2020

PurposeSmall sports clubs are the life-blood of particular communities, even though many are under-resourced and have difficulties in operating under an individualistic business model. Although coopetition (simultaneous cooperation and competition) has been recognised as a positive driver of performance, the complexities of this association remain under-researched. Consequently, grounded in resource-based theory and the relational view, the purpose of this current study is to examine the moderating roles of inter-firm conflict and competitive intensity in the coopetition–sales performance relationship.Design/methodology/approachAfter undertaking 25 field interviews, survey data were collected from 151 non-mainstream sporting clubs in New Zealand. This setting was ideal, since it hosts high-degrees of cooperativeness and competitiveness. After assessing the statistical data for all major robustness checks (including common method variance and endogeneity bias), the hypothesised and control paths were tested through a hierarchical regression analysis.FindingsCoopetition had a positive relationship with sales performance, but inter-firm conflict yielded a negative interaction effect. Surprisingly, this link was positively moderated by competitive intensity.Practical implicationsUnder-resourced entrepreneurs (like those in many small sports clubs) should consider cooperating with their competitors, as these strategies can assist them to improve their sales performance. However, they should be careful when engaging in such activities due to the considerable risk that rival firms could behave opportunistically, which might harm their performance. That being said, owner-managers are advantaged if they operate in sectors where there are lots of competitors because there is increased scope to collaborate with “complementary” and trustworthy rivals that can help them to achieve mutually-beneficial outcomes. Indeed, sporting governing bodies (including those that operate on a non-profit basis) should encourage their members to engage in coopetition due to these positive financial consequences.Originality/valueThis investigation contributes to the extant literature by evaluating the competitive forces affecting the link between coopetition and sales performance. Specifically, new evidence emerges on the circumstances where coopetition is (and is not) a performance-enhancing entrepreneurial strategy. Further, this investigation provides unique insights regarding coopetition among non-mainstream sporting clubs, adding new knowledge to the sports entrepreneurship literature. Moreover, by infusing resource-based theory with the relational view, stronger arguments feature how owner-managers can navigate the paradoxical forces that drive coopetition activities. This study ends with several practitioner implications, alongside a series of limitations and avenues for future research.
Developing a researcher identity of relevance for remote Indigenous language education
Authors: Parfa Koskinen Katarina 
Published: September 2020

PurposeThe study is an elaboration on how a graduate student discursively navigates a research identity through lived experiences as an Indigenous Sámi and writings on Indigenous, as well as other suitable research paradigms informing research on digital technologies in education. The guiding question is how a strategy of inquiry to be used in a PhD study on remote 1–9 Sámi language education can be informed by an Indigenous research paradigm. What philosophical guidelines are needed in navigating a sensitive field of investigation shaped by historical atrocities, discrimination and racist assumptions towards the Sámi people and other Indigenous, marginalised groups?Design/methodology/approachA dialogical approach has been used between readings of mainly Indigenous scholars' writings on the topic and anecdotes illustrating personal experiences from a lived life as Sámi.FindingsThrough this process, a researcher identity has developed, informed by the views from an Indigenous research paradigm that humans are ontologically equal to other entities, and epistemologically knowledge constitutes of relationships between different entities. This makes relationality a central feature of an Indigenous epistemology –not only between people but also including, for example, ideas, history, ancestors, future, artefacts and spirituality – which links epistemology to ontology. The axiological issue of accountability works holistically as “glue”.Originality/valueElucidating underlying arguments and motives behind both an Indigenous research paradigm and the development of researcher identity when designing and planning research is rarely done, which provides the originality of the present contribution.