bluuebunny/crossref_metadata_2025_split huggingface dataset:
An immunogenic model of KRAS-mutant lung cancer for study of targeted therapy and immunotherapy combinations
Authors: Boumelha Jesse , de Carné Trécesson Sophie , Law Emily K. , Romero-Clavijo Pablo , Coelho Matthew A. , Ng Kevin , Mugarza Edurne , Moore Christopher , Rana Sareena , Caswell Deborah R. , Murillo Miguel , Hancock David C. , Argyris Prokopios P. , Brown William L. , Durfee Cameron , Larson Lindsay K. , Vogel Rachel I. , Suárez-Bonnet Alejandro , Priestnall Simon L. , East Philip , Ross Sarah J. , Kassiotis George , Molina-Arcas Miriam , Swanton Charles , Harris Reuben , Downward Julian 
Published: December 2020

ABSTRACTMutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumour regression but ultimately fail to cure these cancers, leading to intense interest in how best to combine them with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumours with the host immune system are inadequate, in part due to the low tumour mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant KRAS-driven lung cancer with an elevated tumour mutational burden by expressing the human DNA cytosine deaminase, APOBEC3B, to mimic the mutational signature seen in human lung cancer. This failed to substantially increase clonal tumour mutational burden and autochthonous tumours remained refractory to immunotherapy. However, by establishing clonal cell lines from these tumours we generated an immunogenic syngeneic transplantation model of KRAS mutant lung adenocarcinoma that was sensitive to immunotherapy. Unexpectedly, we found that anti-tumour immune responses were not directed against neoantigens but instead targeted derepressed endogenous retroviral antigens. The ability of KRASG12Cinhibitors to cause regression of KRASG12C-expressing versions of these tumours was markedly potentiated by the adaptive immune system, providing a unique opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer.
Self-Supervised Representation Learning of Protein Tertiary Structures (PtsRep) and Its Implications for Protein Engineering
Authors: Luo Junwen , Cai Yi , Wu Jialin , Cai Hongmin , Yang Xiaofeng , Lin Zhanglin 
Published: December 2020

AbstractIn recent years, deep learning has been increasingly used to decipher the relationships among protein sequence, structure, and function. Thus far these applications of deep learning have been mostly based on primary sequence information, while the vast amount of tertiary structure information remains untapped. In this study, we devised a self-supervised representation learning framework (PtsRep) to extract the fundamental features of unlabeled protein tertiary structures deposited in the PDB, a total of 35,568 structures. The learned embeddings were challenged with two commonly recognized protein engineering tasks: the prediction of protein stability and prediction of the fluorescence brightness of green fluorescent protein (GFP) variants, with training datasets of 16,431 and 26,198 proteins or variants, respectively. On both tasks, PtsRep outperformed the two benchmark methods UniRep and TAPE-BERT, which were pre-trained on two much larger sets of data of 24 and 32 million protein sequences, respectively. Protein clustering analyses demonstrated that PtsRep can capture the structural signatures of proteins. Further testing of the GFP dataset revealed two important implications for protein engineering: (1) a reduced and experimentally manageable training dataset (20%, or 5,239 variants) yielded a satisfactory prediction performance for PtsRep, achieving a recall rate of 70% for the top 26 brightest variants with 795 variants in the testing dataset retrieved; (2) counter-intuitively, when only the bright variants were used for training, the performances of PtsRep and the benchmarks not only did not worsen but they actually slightly improved. This study provides a new avenue for learning and exploring general protein structural representations for protein engineering.
Functional analysis of caspase cleavable proteoforms from theDrosophilaGSK-3 geneshaggy
Authors: Korona Dagmara , Nightingale Daniel , Fabre Bertrand , Nelson Michael , Fischer Bettina , Johnson Glynnis , Hubbard Simon , Lilley Kathryn , Russell Steven 
Published: December 2020

AbstractTheDrosophila shaggy(sgg) gene encodes the major fly orthologue of Glycogen Synthase Kinase −3 (GSK-3), a key highly conserved kinase at the heart of many signalling pathways. Thesgglocus is complex, encoding multiple protein isoforms that are expressed in distinct temporal and tissue-specific patterns across development. Its isoforms predominantly differ at the carboxy and amino termini due to the use of different transcriptional start sites and alternative splicing events that include internal and terminal exons. One interesting class of proteins isoforms is represented by the Sgg-PD class (Sgg46), three proteoforms that contain a large 582 amino acid N-terminal domain which contains recognition sites for caspase-mediated cleavage. Regulated cleavage at these sites by non-apoptotic caspases has previously been implicated in the regulation of Sgg activity in adult bristle development. Here, we take a genome engineering approach to introduce specific tags into this unique Sgg-PD exon and utilise these for localisation and protein interaction studies. We also generated new loss of function alleles and specific mutations in the caspase cleavage motifs. We find that loss of functions Sgg-PD class alleles are viable and fertile, but exhibit adult locomotor and bristle defects. Expression analysis of lines carrying tags on both sides of the caspase cleavage sites indicates that the cleavage is developmentally regulated during embryogenesis. Surprisingly, we found that in some cells, particularly embryonic hemocytes, the N-terminal domain released by caspase cleavage is retained while the polypeptide containing the conserved kinase domain is apparently lost. Transcriptomic analysis of embryos homozygous for the new caspase-insensitive allele indicates a role for Sgg-PD in the regulation of cytoskeletal and cell junction functions, which is supported by proteomics analysis using specific in locus tags to identify common and unique protein interaction partners with N- and C-terminal domains. Taken together, our work identifies new activities for the Sgg protein and uncovers unexpected roles for caspase cleavage in Sgg biology.
Wild animal oral microbiomes reflect the history of human antibiotics use
Authors: Brealey Jaelle C. , Leitão Henrique G. , Hofstede Thijs , Kalthoff Daniela C. , Guschanski Katerina 
Published: December 2020

AbstractFollowing the advent of industrial-scale antibiotics production in the 1940s, antimicrobial resistance (AMR) has been on the rise and now poses a major global health threat. Because AMR can be exchanged between humans, livestock and wildlife, evaluating the potential of wild animals to act as AMR reservoirs is essential. We used shotgun metagenomics sequencing of dental calculus, the calcified form of the oral microbial biofilm, to determine the abundance and repertoire of AMR genes in the oral microbiome of Swedish brown bears from museum specimens collected over the last 200 years. Our temporal metagenomics approach allowed us to establish a baseline of natural AMR in the pre-antibiotics era and to quantify a significant increase in total AMR load and diversity of AMR genes that is correlated with human antibiotics use. We also demonstrated that Swedish public health policies were effective in limiting AMR spillover into wildlife.
Financial leverage and corporate innovation in Chinese public-listed firms
Authors: Iqbal Najaf , Xu Ju Feng , Fareed Zeeshan , Wan Guangcai , Ma Lina 
Published: December 2020

PurposeThis study attempts to document the impact of financial leverage on corporate innovation in the Chinese nonfinancial public firms listed on Shenzhen and Shanghai stock exchanges.Design/methodology/approachThe firm-level data are collected from CSMAR database for ten years, ranging from 2007 to 2016. The authors have employed the panel fixed effects model and further system GMM approach for analysis. The sample is segregated on the basis of state (SOE) and nonstate ownership (NSOE) to check for the diverse effects. In total, three different proxies of financial leverage are used to unearth the varying impact of short-time and long-term leverage separately. Further, corporate innovation is divided into input innovation (R&D/Sales and R&D/Assets) and output innovation (patents and inventions).FindingsThe results suggest that financial leverage is detrimental to the input innovation while conducive for the output innovation when measured by the number of patents. Contrarily, leverage has a negative influence over the output innovation when measured by the number of inventions. This implies that leverage is more damaging for the highest form of innovativeness (inventions) in China. Input innovation is more sensitive to the changes in long-term leverage versus short-term leverage. Further, the authors find that innovation in SOEs is more sensitive to the changes in the leverage as compared to the NSOEs. The results are free from the threat of endogeneity and identification problems, as reported by the system GMM model.Research limitations/implicationsThe authors did not segregate the sample on the basis of industry/sector.Practical implicationsThe firms pursuing a strategy of radical innovation should try to keep their debt levels lower in order to achieve a higher innovation performance. Although, a rise in the leverage may mean an increased access to finance for a firm but such an access comes at a cost in the form of damage to the corporate innovation. However, increased debt financing may not be so bad for the firms that want to achieve a moderate and not the highest level of innovation. Such firms can produce recurring and synergic effects with debt financing and moderate innovation, once they achieve a level of innovation performance that satisfies their financiers.Originality/valueTo the best of authors’ knowledge, this is probably the first study to check the impact of firm-level financial leverage on both input and output innovation in the Chinese public-listed nonfinancial firms' panel data perspective till now.
Availability modeling and estimation of Fluid Catalytic Cracking Unit using generalized Stochastic Petri Nets
Authors: Gurunathan Thangamani 
Published: December 2020

PurposeThe purpose of this paper to present a practical and systematic approach to estimate the availability of a process plant using generalized stochastic Petri nets (GSPNs). The actual live problem at a fluid catalytic cracking unit (FCCU) of a refinery is used to demonstrate this approach.Design/methodology/approachA majority of models used for estimation of availability of a complex system are based on the assumptions that the failure of the system is associated with only a few states, and the system does not face different operating conditions, repair actions and common-cause failures. In reality, this is often not the case. Therefore, it is necessary to construct more sophisticated models without such assumptions. In this paper, an attempt has been made to model interaction of component failures, partial failures of components and common-cause failures.FindingsThe superiority of this approach over other modeling approaches such as fault tree and Markov analysis is demonstrated. The proposed GSPN is a promising tool that can be conveniently used to model and analyze any complex systems.Practical implicationsGSPN was used to model the reactor-regenerator section of FCCU, which is quite a large system, which shows the strength of modeling capability. The use of Petri nets (PNs) for modeling complex systems for the purpose of availability assessment is demonstrated in this paper. Sensitivity analysis was also carried out for various subsystem/components.Originality/valueNo similar work has been conducted for FCCU using GSPN as per literature incorporating different operating conditions and common-cause failures. The understanding and usage of PNs require a steep learning curve for the practitioners, and this paper provides an approach to estimate availability measures for the complex system.
Facilitation of information literacy through a multilingual MOOC considering cultural aspects
Authors: Dreisiebner Stefan , Polzer Anna Katharina , Robinson Lyn , Libbrecht Paul , Boté-Vericad Juan-José , Urbano Cristóbal , Mandl Thomas , Vilar Polona , Žumer Maja , Juric Mate , Pehar Franjo , Stričević Ivanka 
Published: December 2020

PurposeThe purpose of this paper is to demonstrate the rationale, technical framework, content creation workflow and evaluation for a multilingual massive open online course (MOOC) to facilitate information literacy (IL) considering cultural aspects.Design/methodology/approachA good practice analysis built the basis for the technical and content framework. The evaluation approach consisted of three phases: first, the students were asked to fill out a short self-assessment questionnaire and a shortened adapted version of a standardized IL test. Second, they completed the full version of the IL MOOC. Third, they were asked to fill out the full version of a standardized IL test and a user experience questionnaire.FindingsThe results show that first the designed workflow was suitable in practice and led to the implementation of a full-grown MOOC. Second, the implementation itself provides implications for future projects developing multilingual educational resources. Third, the evaluation results show that participants achieved significantly higher results in a standardized IL test after attending the MOOC as mandatory coursework. Variations between the different student groups in the participating countries were observed. Fourth, self-motivation to complete the MOOC showed to be a challenge for students asked to attend the MOOC as nonmandatory out-of-classroom task. It seems that multilingual facilitation alone is not sufficient to increase active MOOC participation.Originality/valueThis paper presents an innovative approach of developing multilingual IL teaching resources and is one of the first works to evaluate the impact of an IL MOOC on learners' experience and learning outcomes in an international evaluation study.
Behavioral routes to loyalty across gender on m-banking usage
Authors: Windasari Nila Armelia , Albashrawi Mousa 
Published: December 2020

Purpose
Despite merely comparing constructs on male vs female, this study aims to explore how customer usage behavior to loyalty journey is generated by both service providers and the individual factors.

Design/methodology/approach
The authors survey 516 m-banking customers and test the hypotheses using partial least squares structural equation modeling. Structural equation modeling analysis was used because of its capability to handle several exogenous and endogenous variables. All variables were adapted from established constructs in information systems literature.

Findings
The results show different routes of loyalty between male vs female. Males emphasize system and information qualities to shape expectancies as well as facilitating conditions that in turn affect males’ loyalty. While in females, service quality plays a big role in shaping their satisfaction, and in turn affects female customer loyalty.

Originality/value
The study of gender and technology usage has been growing since decades. With higher technological advancement, people always demand for higher service experience and customer behavior evolves accordingly. Although earlier studies on technology adoption models have received considerable empirical validation, most of the studies did not consider different routes across gender.
Mimicking Behçet's disease: GM-CSF gain of function mutation in a family suffering from a Behçet's disease-like disorder marked by extreme pathergy
Authors: Rösler B , Heinhuis B , Wang X , Silvestre R , Joosten L A B , Netea M G , Arts P , Mantere T , Lefeber D J , Hoischen A , Veerdonk F L 
Published: December 2020

Summary
Behçet's disease (BD) is an inflammatory disease mainly affecting men along the ancient Silk Route. In the present study we describe a Dutch family suffering from BD-like disease with extreme pathergic responses, but without systemic inflammation. Genetic assessment revealed a combination of the human leukocyte antigen (HLA)-B*51 risk-allele together with a rare heterozygous variant in the CSF2 gene (c.130A&gt;C, p.N44H) encoding for granulocyte–macrophage colony-stimulating factor (GM-CSF) found by whole exome sequencing. We utilized an over-expression vector system in a human hepatocyte cell line to produce the aberrant variant of GM-CSF. Biological activity of the protein was measured by signal transducer and activator of transcription 5 (STAT-5) phosphorylation, a downstream molecule of the GM-CSF receptor, in wild-type peripheral mononuclear cells (PBMCs) using flow cytometry. Increased STAT-5 phosphorylation was observed in response to mutated GM-CSF when compared to the wild-type or recombinant protein. CSF2 p.N44H results in disruption of one of the protein's two N-glycosylation sites. Enzymatically deglycosylated wild-type GM-CSF also enhanced STAT-5 phosphorylation. The patient responded well to anti-tumor necrosis factor (TNF)-α treatment, which may be linked to the capacity of TNF-α to induce GM-CSF in phorbol 12-myristate 13-acetate (PMA)-treated PBMCs, while GM-CSF itself only induced dose-dependent interleukin (IL)-1Ra production. The identified CSF2 pathway could provide novel insights into the pathergic response of BD-like disease and offer new opportunities for personalized treatment.
An analysis of the prevalence of osteoporosis and osteopenia in patients with epidermolysis bullosa: A cross‐sectional study
Authors: Kang Mina , Chen Jessica S. C. , Radjenovic Melissa , Yang Anes , Feng Grant H. Y. , Murrell Dedee F. 
Published: December 2020

AbstractBackgroundEpidermolysis bullosa (EB) patients have multiple risk factors for osteoporosis. There is limited literature describing the prevalence of bone health in EB, particularly in adults and less severe EB types.ObjectivesTo investigate the prevalence of osteopenia or osteoporosis in EB patients from the Australasian Epidermolysis Bullosa Registry (AEBR).MethodsOf 417 AEBR patients, 72 underwent a dual energy X‐ray absorptiometry scan. Bone mineral density (BMD) T and Z‐scores, EB Disease Activity and Scarring Index (EBDASI), and Quality of Life in EB (QOLEB) scores were obtained.ResultsT‐scores of RDEB patients were significantly lower than the diagnostic cut‐off value for osteopenia. EBDASI and QOLEB scores were inversely correlated with Z‐scores. The prevalence of osteoporosis in adults was 75% in severe EB types (RDEB and JEB). In adults with less severe types (EBS and DDEB), the prevalence of osteopenia was 50% and 33%, respectively.ConclusionsThis is the largest study of osteoporosis in EB to date and the first to include adult patients with EBS. The high prevalence of osteoporosis and osteopenia identified in these patients warrants larger, collaborative international studies. Nevertheless, EB patients with high disease severity and QOL scores, irrespective of type, should receive early osteoporosis screening and prophylaxis.
The multi‐functional RNA‐binding protein G3BP1 and its potential implication in neurodegenerative disease
Authors: Sidibé Hadjara , Dubinski Alicia , Vande Velde Christine 
Published: December 2020

AbstractRas‐GTPase‐activating protein (GAP)‐binding protein 1 (G3BP1) is a multi‐functional protein that is best known for its role in the assembly and dynamics of stress granules. Recent studies have highlighted that G3BP1 also has other functions related to RNA metabolism. In the context of disease, G3BP1 has been therapeutically targeted in cancers because its over‐expression is correlated with proliferation of cancerous cells and metastasis. However, evidence suggests that G3BP1 is essential for neuronal development and possibly neuronal maintenance. In this review, we will examine the many functions that are carried out by G3BP1 in the context of neurons and speculate how these functions are critical to the progression of neurodegenerative diseases. Additionally, we will highlight the similarities and differences between G3BP1 and the closely related protein G3BP2, which is frequently overlooked. Although G3BP1 and G3BP2 have both been deemed important for stress granule assembly, their roles may differ in other cellular pathways, some of which are specific to the CNS, and presents an opportunity for further exploration.
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Comparing risk factors associated with the late detection of critical congenital heart disease at different facility levels
Authors: Sotodate Genichiro , Oyama Kotaro , Saiki Hirofumi , Matsumoto Atsushi , Konishi Yu , Toya Yukiko , Takashimizu Nao , Tsuchiya Shigekuni 
Published: December 2020

AbstractAimsCritical congenital heart disease (CCHD) requires surgery or catheter intervention within the first year of life; delayed diagnoses result in worsened outcomes. In Japan, there are few reports of delayed CCHD diagnosis. We investigated the diagnoses and factors associated with the late detection of CCHD.MethodsThis retrospective cohort study evaluated 88 CCHD infants admitted to a level IV facility. We compared the late detection rates across facility levels of neonatal care and CCHD characteristics.ResultsCritical congenital heart disease was identified prenatally in 46 (52%) infants: early (≤3 days postnatally) in 29 (33%) and late (≥4 days postnatally) in 13 (15%). The oxygen saturation of 27 of 29 infants with early detection and 7 of 13 infants with late detection was measured using pulse oximetry within 3 days postnatally. Factors associated with the late detection of CCHD were lack of clinical recognition of symptoms in five infants, referral to higher‐level facilities after discharge in four infants, and definitive diagnosis not confirmed using echocardiography in four infants. The most common factors associated with late detection were referral to higher‐level facilities after discharge in level I facilities and definitive diagnosis not confirmed using echocardiography in level II facilities.ConclusionCritical congenital heart disease may require advanced knowledge and echocardiographic techniques for diagnosis. Pulse oximetry and telemedicine should also be incorporated in the diagnostic algorithm. Improvement in these factors might contribute to reducing the late detection of CCHD.