bluuebunny/crossref_metadata_2025_split huggingface dataset:
Were the floods in the UK 2007 and Germany 2013 game-changers?
Authors: Platt Stephen , Mahdavian Farnaz , Carpenter Oliver , Wiens Marcus , Schultmann Frank 
Published: February 2020

This paper examines recovery after major floods in the UK and Germany. It focuses on two areas that were badly hit by flooding: Catcliffe, near Sheffield in the UK, and Passau in Bavaria, Germany. It reports on surveys of residents and businesses in each place and on surveys of national flood experts in both countries. The two events were comparable in terms of impacts, levels of preparedness and government response and show similar patterns of speed and quality of recovery. In Germany, it took about 18 months for 90% or more of residents to get back to normal, while in the UK it took a year longer. This difference may be related to funding; in the UK, over 90% of funding came from household insurance while in Germany over 60% came from federal aid, which may have been quicker. In both countries, the economy had recovered to near normal within 12–18 months. The majority of people surveyed in both countries (74% in Germany and 67% in the UK) believe that their homes and businesses are as just as vulnerable now as they were before the respective floods. However, in the UK, half of the respondents thought their neighbourhood was safer and better prepared compared to only 11% in Germany. This may be because substantial progress has been made in improving protection in the UK in areas flooded in 2007. Both floods were considered to be ‘game-changers’ and resulted in a heightened awareness of flood risk, increased investment in flood defences and an increasing emphasis on citizens taking more responsibility for flood preparedness. However, the Environment Agency in the UK lacks powers to prevent development in flood-prone areas, in Germany there are issues of coordination across large catchments that cross state boundaries and the insurance sector could play a bigger role in ‘building back better’. Many homes and businesses continue to be at risk from major floods and more progress needs to be made in making them more resilient.This article is part of the theme issue ‘Urban flood resilience’.
A NKp80-based identification strategy reveals that CD56negNK cells are not completely dysfunctional in health and disease
Authors: Orrantia Ane , Terrén Iñigo , Izquierdo-Lafuente Alicia , Alonso-Cabrera Juncal A. , Sandá Victor , Vitallé Joana , Moreno Santiago , Tasias María , Uranga Alasne , González Carmen , Mateos Juan J. , García-Ruiz Juan C. , Zenarruzabeitia Olatz , Borrego Francisco 
Published: February 2020

ABSTRACTNatural killer (NK) cells are usually identified by the absence of other lineage markers, due to the lack of a cell surface specific marker. CD56negNK cells, classically identified as CD56negCD16+are known to be expanded in some pathological conditions. However, studies on CD56negNK cells had revealed different results regarding the phenotype and functionality of these cells. This could be due to, among others, the unstable expression of CD16, which hinders CD56negNK cells identification. Hence, we aim to determine an alternative surface marker to CD16 to better identify CD56negNK cells. Using multiparametric flow cytometry, we have found that NKp80 is a good alternative to CD16 not only in healthy donors but also in HIV-1 infected subjects and multiple myeloma patients. Furthermore, we found differences between the functionality of CD56negNKp80+and CD56negCD16+NK cells both in healthy donors and patients, suggesting that the effector functions of CD56negNK cells are not as diminished as previously thought. We proposed NKp80 as a noteworthy marker to identify and accurately re-characterize human CD56negNK cells.
The dynamic interplay of host and viral enzymes in type III CRISPR-mediated cyclic nucleotide signalling
Authors: Athukoralage Januka S. , Graham Shirley , Rouillon Christophe , Grüschow Sabine , Czekster Clarissa M. , White Malcolm F. 
Published: February 2020

AbstractCyclic nucleotide second messengers are increasingly implicated in prokaryotic anti-viral defence systems. Type III CRISPR systems synthesise cyclic oligoadenylate (cOA) upon detecting foreign RNA, activating ancillary nucleases that can be toxic to cells, necessitating mechanisms to remove cOA in systems that operate via immunity rather than abortive infection. Previously, we demonstrated that theSulfolobus solfataricustype III-D CRISPR complex generates cyclic tetra-adenylate (cA4), activating the ribonuclease Csx1, and showed that subsequent RNA cleavage and dissociation acts as an “off-switch” for the cyclase activity (Rouillonet al., 2018). Subsequently, we identified the cellular ring nuclease Crn1, which slowly degrades cA4to reset the system, and demonstrated that viruses can subvert type III CRISPR immunity by means of a potent anti-CRISPR ring nuclease variant. Here, we present a comprehensive analysis of the dynamic interplay between these enzymes, governing cyclic nucleotide levels and infection outcomes in virus-host conflict.
Optimizing diagnostic strategy for novel coronavirus pneumonia, a multi-center study in Eastern China
Authors: Ai Jing-Wen , Zhang Hao-Cheng , Xu Teng , Wu Jing , Zhu Mengqi , Yu Yi-Qi , Zhang Han-Yue , Li Yang , Zhou Xian , Shen Zhongliang , Zang Guo-Qing , Xu Jie , Chen Wen-Jing , Li Yong-Jun , Xie De-Sheng , Zhou Ming-Zhe , Sun Jing-Ying , Chen Jia-Zhen , Zhang Wen-Hong 
Published: February 2020

AbstractCOVID-19 caused by a novel coronavirus SARS-CoV-2 emerged in Wuhan, Hubei province since December 2019, and caused a rapid outbreak throughout China and globally. Cities outside Hubei are also facing great challenge and require implementing of effective and feasible strategy in precision diagnosing novel coronavirus pneumonia (NCP).We described a multicenter prospective study on diagnostic strategy of suspected NCP patients from January 22nd to February 9th, 2020 in Eastern China cities. Nasopharyngeal swabs were collected from the patients. The epidemiological characteristics, clinical symptoms, laboratory assessments, and computed tomographic (CT) scans were obtained. Pathogen screen were performed including RT-PCR, multiplex PCR, rapid flu antigen tests and mNGS.We enrolled 53 suspected NCP patients, among whom 20 were laboratory-confirmed. Fourteen (70%) and 3 (15%) patients were positive for the first and second SARS-CoV-2 RT-PCR test, respectively. All NCP patients were positive for mNGS. Chest CT images and the symptoms of early stage NCP patients were similar to other viral pneumonia patients. We identified 11 of 20 co-infections in NCP cases, including regular respiratory virus, fungi and bacteria synchronously. Genomic analysis showed that 8 of 10 cases had no mutation in virus genome, while 2 cases had only one single mutation in N gene.Our study discovered that a combination of chest CT, SARS-CoV-2 RT-PCR and multi-plex PCR is recommended in regions outside Hubei province. Co-infection of other pathogens with SARS-CoV-2 exists and should be acknowledged. Repeated sampling, change of specimen type or metagenomics sequencing could further facilitate during critical clinical cases.
Modeling the post-translational modifications and its effects in the NF-κB pathway
Authors: Mobeen Ahmed , Ramachandran Srinivasan 
Published: February 2020

AbstractThe transcriptional activities of NFKB1 and NFKB2 complexes are regulated by several post-translational modifications at different sites of these complexes. The post-translational modifications reported in the literature include phosphorylation, methylation, acetylation, sulphydration, nitrosylation, ubiquitination and sumoylation. We present a pathway network model with 172 proteins, 313 molecular species and 476 reactions including degradation of IkB (NFKBIA), proteolytic processing, and posttranslational modifications on p65 (RELA), RELB, p50 (NFKB1), and p52 (NFKB2) proteins. Comparing with experimental data on the over expression or knockouts of specific genes afforded qualitative agreement between model predictions and the experimental results. NFKB1:RELA complex is activated by active IKBKB, PIN1, MAP3K14 but repressed by PPARG and PDLIM2. MAP3K14 and UBE2I enhance the NFKB2:RELB activity, whereas NLRP12 is its repressor. The constitutive activation of NFKB1 complex through positive regulation of group of cytokines (IL1, IL1B and IL6) and IKK complex (alpha, beta and gamma) could be annulled by activation of PPARG, PIAS3 and P50-homodimer together instead of individual activations. Thus, the presented network pathway model has predictive utility in inferring NF-κB activity.
Democratizing water monitoring: Implementation of a community-based qPCR monitoring program for recreational water hazards
Authors: Rudko Sydney P , Reimink Ronald R , Peter Bradley , White Jay , Hanington Patrick C 
Published: February 2020

AbstractRecreational water monitoring can be challenging due to the highly variable nature of pathogens and indicator concentrations, the myriad of potential biological hazards to measure for, and numerous access points, both official and unofficial, that are used for recreation. The aim of this study was to develop, deploy, and assess the effectiveness of a quantitative polymerase chain reaction (qPCR) community-based monitoring (CBM) program for the assessment of bacterial and parasitic hazards in recreational water. This study developed methodologies for performing qPCR ‘in the field’, then engaged with water management and monitoring groups, and tested the method in a real-world implementation study to evaluate the accuracy of CBM using qPCR both quantitatively and qualitatively. This study found high reproducibility between qPCR results performed by non-expert field users and expert laboratory results, suggesting that qPCR as a methodology could be amenable to a CBM program.
Gene expression noise can promote the fixation of beneficial mutations in fluctuating environments
Authors: Schmutzer Michael , Wagner Andreas 
Published: February 2020

AbstractNongenetic phenotypic variation can either speed up or slow down adaptive evolution. We show that it can speed up evolution in environments in which available carbon and energy sources change over time. To this end, we use an experimentally validated model ofEscherichia coligrowth on two alternative carbon sources, glucose and acetate. On the superior carbon source (glucose), all cells achieve high growth rates, while on the inferior carbon source (acetate) only a small fraction of the population manages to initiate growth. Consequently, populations experience a bottleneck when the environment changes from the superior to the inferior carbon source. Growth on the inferior carbon source depends on a circuit under the control of a transcription factor that is repressed in the presence of the superior carbon source. We show that noise in the expression of this transcription factor can increase the probability that cells start growing on the inferior carbon source. In doing so, it can decrease the severity of the bottleneck and increase mean population fitness whenever this fitness is low. A modest amount of noise can also enhance the fitness effects of a beneficial allele. It can accelerate the spreading of such an allele, increase its likelihood of going to fixation, and reduce its fixation time. Central to the adaptation-enhancing principle we identify is the ability of noise to mitigate population bottlenecks. Because such bottlenecks are frequent in fluctuating environments, and because fluctuating environments themselves are ubiquitous, this principle may apply to a broad range of environments and organisms.Author summaryIndividuals that grow in the same environment and share the same genes may still differ in their behaviour and their traits. These differences between individuals arise from uncertainty inherent in all biological processes, and they are found in all domains of life. Although this random individual variability is itself short-lived, it still has the potential to shape evolution in the long term. For example, if a population encounters a harsh environment, random (nongenetic) differences between individuals can cause some individuals to cope better with the new environment than others. These rare individuals may give a population an advantage compared to populations with fewer such differences between individuals. Furthermore, if some of these rare individuals carry a beneficial gene variant, the beneficial effect of this gene variant may become amplified, and consequently spread faster in a population with more random variation. Using a realistic model of cell growth, we show that this mechanism not only works in unfavourable environments that are stable, but also in environments that switch back and forth between a favourable and an unfavourable state. Because many natural environments undergo such periodic changes, and because random differences between individuals are ubiquitous, the mechanism we have identified may be widespread in nature.
Formicine ants swallow their highly acidic poison for gut microbial selection and control
Authors: Tragust Simon , Herrmann Claudia , Häfner Jane , Braasch Ronja , Tilgen Christina , Hoock Maria , Milidakis Margarita Artemis , Gross Roy , Feldhaar Heike 
Published: February 2020

AbstractAnimals continuously encounter microorganisms that are essential for health or cause disease. They are thus challenged to control harmful microbes while allowing acquisition of beneficial microbes. This challenge is likely especially important for social insects with respect to microbes in food, as they often store food and exchange food among colony members. Here we show that formicine ants actively swallow their antimicrobial, highly acidic poison gland secretion. The ensuing acidic environment in the stomach, the crop, limits establishment of pathogenic and opportunistic microbes ingested with food and improves survival of ants when faced with pathogen contaminated food. At the same time, crop acidity selectively allows acquisition and colonization by Acetobacteraceae, known bacterial gut associates of formicine ants. This suggests that swallowing of the poison gland secretion acts as a microbial filter in formicine ants and indicates a potentially widespread but so far underappreciated dual role of antimicrobials in host-microbe interactions.
ToxoplasmaGRA15 and GRA24 are important activators of the host innate immune response in the absence of TLR11
Authors: Mukhopadhyay Debanjan , Arranz-Solís David , Saeij Jeroen P.J. 
Published: February 2020

AbstractThe murine innate immune response againstToxoplasma gondiiis predominated by the interaction of TLR11/12 withToxoplasmaprofilin. However, mice lackingTlr11or humans, who do not have functional TLR11 or TLR12, still elicit a strong innate immune response uponToxoplasmainfection. The parasite factors that determine this immune response are largely unknown. Herein, we investigated two dense granule proteins (GRAs) secreted byToxoplasma,GRA15 and GRA24, for their role in stimulating the innate immune response inTlr11-/-mice and in human cells, which naturally lack TLR11/TLR12. Our results show that GRA15 and GRA24 synergistically shape the early immune response and parasite virulence inTlr11-/-mice, with GRA15 as the predominant effector. Nevertheless, acute virulence inTlr11-/-mice is still dominated by allelic combinations ofROP18andROP5, which are effectors that determine evasion of the immunity-related GTPases. In human macrophages, GRA15 and GRA24 play a major role in the induction of IL12, IL18 and IL1β secretion. We further show that GRA15/GRA24-mediated IL12, IL18 and IL1β secretion activates IFNγ secretion by peripheral blood mononuclear cells (PBMCs), which controlsToxoplasmaproliferation. Taken together, our study demonstrates the important role of GRA15 and GRA24 in activating the innate immune response in hosts lacking TLR11.ImportanceIn mice, the early immune response againstToxoplasmais dominated by TLR11-mediated release of IL-12, which subsequently induces protective IFNγ. Here we show that inTlr11-/-mice and in human cells, which do not have TLR11, theToxoplasmaGRA15 and GRA24 effectors play an important role in induction of IL12, IL18 and IL1β, and thus in the subsequent protective IFNγ secretion.
Promoter CpG density predicts downstream gene loss-of-function intolerance
Authors: Boukas Leandros , Bjornsson Hans T. , Hansen Kasper D. 
Published: February 2020

AbstractThe aggregation and joint analysis of large numbers of exome sequences has recently made it possible to de-rive estimates of intolerance to loss-of-function (LoF) variation for human genes. Here, we demonstrate strong and widespread coupling between genic LoF-intolerance and promoter CpG density across the human genome. Genes downstream of the most CpG-rich pro-moters (top 10% CpG density) have a 67.2% probability of being highly LoF-intolerant, using the LOEUF metric from gnomAD. This is in contrast to 7.4% of genes downstream of the most CpG-poor (bottom 10% CpG density) promoters. Combining promoter CpG density with exonic and promoter conservation explains 33.4% of the variation in LOEUF, and the contribution of CpG density exceeds the individual contributions of exonic and promoter conservation. We leverage this to train a simple and easily interpretable predictive model that out-performs other existing predictors and allows us to classify 1,760 genes – which currently lack reliable LOEUF estimates – as highly LoF-intolerant or not. These predictions have the potential to aid in the interpretation of novel patient variants. Moreover, our results reveal that high CpG density is not merely a generic feature of human promoters, but is preferentially encountered at the promoters of the most selectively constrained genes, calling into question the prevailing view that CpG islands are not subject to selection.
AS-Quant: Detection and Visualization of Alternative Splicing Events with RNA-seq Data
Authors: Fahmi Naima Ahmed , Yeh Hsin-Sung , Chang Jae-Woong , Nassereddeen Heba , Fan Deliang , Yong Jeongsik , Zhang Wei 
Published: February 2020

AbstractA simplistic understanding of the central dogma falls short in correlating the number of genes in the genome to the number of proteins in the proteome. Post-transcriptional alternative splicing contributes to the complexity of proteome and are critical in understanding gene expression. mRNA-sequencing (RNA-seq) has been widely used to study the transcriptome and provides opportunity to detect alternative splicing events among different biological conditions. Despite the popularity of studying transcriptome variants with RNA-seq, few efficient and user-friendly bioinformatics tools have been developed for the genome-wide detection and visualization of alternative splicing events. We have developed AS-Quant (AlternativeSplicingQuantitation), a robust program to identify alternative splicing events and visualize the short-read coverage with gene annotations. AS-Quant works in three steps: (i) calculate the read coverage of the potential splicing exons and the corresponding gene; (ii) categorize the splicing events into five different types based on annotation, and assess the significance of the events between two biological conditions; (iii) generate the short reads coverage plot with a complete gene annotation for user specified splicing events. To evaluate the performance, two significant alternative splicing events identified by AS-Quant between two biological contexts were validated by RT-PCR.ImplementationAS-Quant is implemented in Python. Source code and a comprehensive user’s manual are freely available athttps://github.com/CompbioLabUCF/AS-Quant
Solubility-Weighted Index: fast and accurate prediction of protein solubility
Authors: Bhandari Bikash K. , Gardner Paul P. , Lim Chun Shen 
Published: February 2020

ABSTRACTMotivationRecombinant protein production is a widely used technique in the biotechnology and biomedical industries, yet only a quarter of target proteins are soluble and can therefore be purified.ResultsWe have discovered that global structural flexibility, which can be modeled by normalised B-factors, accurately predicts the solubility of 12,216 recombinant proteins expressed inEscherichia coli. We have optimised B-factors, and derived a new set of values for solubility scoring that further improves prediction accuracy. We call this new predictor the ‘Solubility-Weighted Index’ (SWI). Importantly, SWI outperforms many existing protein solubility prediction tools. Furthermore, we have developed ‘SoDoPE’ (Soluble Domain for Protein Expression), a web interface that allows users to choose a protein region of interest for predicting and maximising both protein expression and solubility.AvailabilityThe SoDoPE web server and source code are freely available athttps://tisigner.com/sodopeandhttps://github.com/Gardner-BinfLab/TISIGNER-ReactJS, respectively. The code and data for reproducing our analysis can be found athttps://github.com/Gardner-BinfLab/SoDoPE_paper2020.
Development of a novel allograft model of prostate cancer: a new tool to inform clinical translation
Authors: Haughey Charles M. , Mukherjee Debayan , Steele Rebecca E. , Popple Amy , Dura-Perez Lara , Pickard Adam , Jain Suneil , Mullan Paul B. , Williams Rich , Oliveira Pedro , Buckley Niamh E. , Honeychurch Jamie , McDade Simon , Illidge Timothy , Mills Ian G. , Eddie Sharon L. 
Published: February 2020

AbstractBackgroundAllograft models enable characterisation of genomic drivers and treatment responses by modelling immune and micro-environmental changes more accurately than xenografts. Despite this, few models are available to the prostate cancer (PCa) community. This study presents a novel allograft model of high-risk, localised PCa. In characterising this model we have focused on its response to radiotherapy (RT).MethodsThe DVL3 cell line was derived from a transgenic trp53-/-/Pten-/-mouse model and characterised bothin vitroandin vivo. The DVL3 cells were allografted and response to RT was investigated and compared to the TRAMP-C1 model. Extensive tumour profiling in the DVL3 model was performed using flow cytometry, immunohistochemistry and RNA-seq.ResultsIn vitrothe DVL3 cells expressed basal and luminal markers. DVL3 cells formed tumours with distinct glandular morphology which expressed androgen receptor, similar to human localised PC. DVL3 tumour growth was delayed following administration of fractionated RT, with infiltration of myeloid derived suppressor cells (MDSC).ConclusionsThe DVL3 allograft model represents substantial progress in PCa modelling, displaying; luminal differentiation, strong AR expression, and an immunosuppressive microenvironment, similar to observations in high-risk PCa patients. This model is ideally suited for development and validation of novel therapeutics, in particular immune-modulatory agents in combination with RT.