bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk Factors of Mortality of Hospitalised Adult Burn Patients a Malawian Tertiary Hospital Burns Unit
Authors: Kasenda Stephen , Mategula Donnie , Manda Geoffrey Elihu , Chokotho Tilinde Keith 
Published: September 2018

ABSTRACTIntroductionMalawi has the highest rates of mortality directly or indirectly associated with burn injuries in Southern Africa. There is however no published literature on risk factors of mortality among adult patients.MethodsWe conducted a retrospective cross sectional audit records of patients admitted at the burns unit of Queen Elizabeth Central Hospital (QECH) between the years 2007 and 2017. Death due to burns was our outcome of interest. We collected patient data including demographic information, details of the burn injury and its management and determined how these factors were associated with the risk of death using Person Chi square tests in a univariate analysis and likelihood ratio tests in a multivariate logistic regression model. We also determined the odds ratios of death within the categories of the risk factors after adjusting for important variables using a logistic regression model.ResultsAn analysis of 500 burns patient records showed that 132(26.4%) died during the 10-year period. The lethal area for 50% of burns (LA50) was 28.75% and mortality reached 100% at 40% total burn surface area. The following variables were found to be significantly associated with mortality after controlling for confounders: scalds (OR 0.13; 95% CI 0.05-0.33; <0.0001), increasing total burn surface area (p<0.0001), time lapse to hospital presentation between 48 hours and one week(OR 0.27; 95%CI 0.11-0.68; <0.0001), inhalation burns (OR 5.2; 95% CI 2.0-13.3 p 0.0004) and length of hospital stay greater than two months (OR 0.04 95, CI 0.01-0.15; P<0.0001).ConclusionsRisk factors for mortality are connected by their association with post-burn hypermetabolism. Further studies to are needed to identify the best and cost-effective ways of preventing death in burn patients.
Dynamic Processing of Displacement Loops During Recombinational DNA Repair
Authors: Piazza Aurèle , Shah Shanaya , Wright William Douglass , Gore Steven K. , Koszul Romain , Heyer Wolf-Dietrich 
Published: September 2018

AbstractDisplacement-loops (D-loops) are pivotal intermediates of homologous recombination (HR), a universal DNA double strand break (DSB) repair pathway. We developed a versatile assay for the physical detection of D-loopsin vivo, which enabled studying the kinetics of their formation and defining the network of D-loop formation and reversal pathways. Nascent D-loops are detected within 2 hrs of DSB formation and extended over the next 2 hrs in a system allowing break-induced replication. The majority of D-loops are disrupted in wild type cells by two pathways: one supported by the Srs2 helicase and the other by the Mph1 helicase and the Sgs1-Top3-Rmi1 helicase-topoisomerase complex. Both pathways operate without significant overlap and are delineated by the Rad54 paralog Rdh54 in an ATPase-independent fashion. This study uncovers a novel layer of HR control in cells relying on nascent D-loop dynamics, revealing unsuspected complexities, and identifying a surprising role for a conserved Rad54 paralog.
Paternal knockdown of tRNA (cytosine-5-)-methyltransferase (Dnmt2) increases offspring susceptibility to infection in red flour beetles
Authors: Schulz Nora K E , Mohamed Fakry F. , Lo Lai Ka , Peuß Robert , de Buhr Maike F , Kurtz Joachim 
Published: September 2018

AbstractIntergenerational effects from fathers to offspring are increasingly reported from diverse organisms, but the underlying mechanisms remain speculative. Paternal trans-generational immune priming (TGIP) was demonstrated in the red flour beetle Tribolium castaneum: non-infectious bacterial exposure of fathers protects their offspring against an infectious challenge for at least two generations. Epigenetic processes, such as cytosine methylation of nucleic acids, have been proposed to enable transfer of information from fathers to offspring. Here we studied a potential role in TGIP of the Dnmt2 gene (renamed as Trdmt1 in humans), which encodes a highly conserved enzyme that methylates different RNAs, including specific cytosines of a set of tRNAs. Dnmt2 has previously been reported to be involved in intergenerational epigenetic inheritance in mice and protection against viruses in fruit flies. We first studied gene expression and found that Dnmt2 is expressed in various life history stages and tissues of T. castaneum, with high expression in the reproductive organs. RNAi-mediated knockdown of Dnmt2 in fathers was systemic, slowed down offspring larval development and increased mortality of the adult offspring upon bacterial infection. However, these effects were independent of bacterial exposure of the fathers. In conclusion, our results point towards a role of Dnmt2 for paternal effects, while elucidation of the mechanisms behind paternal TGIP needs further studies.
Rare genetic variation and balanced polymorphisms are important for survival in global change conditions
Authors: Brennan Reid S. , Garrett April D. , Huber Kaitlin E. , Hargarten Heidi , Pespeni Melissa H. 
Published: September 2018

AbstractStanding genetic variation is important for population persistence in extreme environmental conditions. While some species may have the capacity to adapt to predicted average future global change conditions, the ability to survive extreme events is largely unknown. We used single generation selection experiments on hundreds of thousands ofStrongylocentrotus purpuratussea urchin larvae generated from wild-caught adults to identify adaptive genetic variation responsive to moderate (pH 8.0) and extreme (pH 7.5) low pH conditions. Sequencing genomic DNA from pools of larvae, we identified consistent changes in allele frequencies across replicate cultures of both conditions and observed increased linkage disequilibrium around selected loci, revealing selection on recombined standing genetic variation. We found that loci responding uniquely to either selection regime were at low starting allele frequencies while variants that responded to both pH conditions (11.6% of selected variants) started at high frequencies. Loci under selection performed functions related to energetics, pH tolerance, cell growth, and actin/cytoskeleton dynamics. These results highlight that persistence in future conditions will require two classes of genetic variation: common, pH-responsive variants maintained by balancing selection in a heterogeneous environment, and rare variants, particularly for extreme conditions, that must be maintained by large population sizes.
Impact of cancer mutational signatures on transcription factor motifs in the human genome
Authors: Chan Calvin Wing Yiu , Gu Zuguang , Bieg Matthias , Eils Roland , Herrmann Carl 
Published: September 2018

ABSTRACTBackgroundSomatic mutations in cancer genomes occur through a variety of molecular mechanisms, which contribute to different mutational patterns. To summarize these, mutational signatures have been defined using a large number of cancer genomes, and related to distinct mutagenic processes. Each cancer genome can be compared to this reference dataset and its exposure to one or the other signature be determined. Given the very different mutational patterns of these signatures, we anticipate that they will have distinct impact on genomic elements, in particular motifs for transcription factor binding sites (TFBS).ResultsIn this work, we build the link between mutational signatures and TFBS motif alterations. We investigated and computed the theoretical impact of mutational signatures on 512 TFBS motifs, hence translating the trinucleotide mutation frequencies of the signatures into alteration frequencies of specific TFBS motifs, leading either to creation of disruption of these motifs. We further build a theoretical prediction of the alteration patterns for different cancer types based on the exposure of these cancer types to the mutation signatures. For certain motifs, a high correlation is observed between the TFBS motif creation and disruption events related to the information content of the motif.ConclusionOur results show that the mutational signatures have different impact on the binding motifs of transcription factors and that for certain high complexity motifs there is a strong correlation between creation and disruption, related to the information content of the motif. This study represents a background estimation of the alterations due purely to mutational signatures in the absence of additional contributions, e.g. from evolutionary processes.
Comprehensive transcriptomic analysis of cell lines as models of primary tumor samples across 22 tumor types
Authors: Yu K. , Chen B. , Aran D. , Charalel J. , Butte A. , Goldstein T. , Sirota M. 
Published: September 2018

AbstractCancer cell lines are commonly used as models for cancer biology. While they are limited in their ability to capture complex interactions between tumors and their surrounding environment, they are a cornerstone of cancer research and many important findings have been discovered utilizing cell line models. Not all cell lines are appropriate models of primary tumors, however, which may contribute to the difficulty in translatingin vitrofindings to patients. Previous studies have leveraged public datasets to evaluate cell lines as models of primary tumors, but they have been limited in scope to specific tumor types and typically ignore the presence of tumor infiltrating cells in the primary tumor samples. We present here a comprehensive pan-cancer analysis utilizing approximately 9,000 transcriptomic profiles from The Cancer Genome Atlas and the Cancer Cell Line Encyclopedia to evaluate cell lines as models of primary tumors across 22 different tumor types. After adjusting for tumor purity in the primary tumor samples, we performed correlation analysis and differential gene expression analysis between the primary tumor samples and cell lines. We found that cell-cycle pathways are consistently upregulated in cell lines, while no pathways are consistently upregulated across the primary tumor samples. In a case study, we compared colorectal cancer cell lines with primary tumor samples across the colorectal subtypes and identified three colorectal cell lines that were derived from fibroblasts rather than tumor epithelial cells. Lastly, we propose a new set of cell lines panel, the TCGA-110, which contains the most representative cell lines from 22 different tumor types as a more comprehensive and informative alternative to the NCI-60 panel. Our analysis of the other tumor types are available in our web app (http://comphealth.ucsf.edu/TCGA110) as a resource to the cancer research community, and we hope it will allow researchers to select more appropriate cell line models and increase the translatability ofin vitrofindings.
Photo-inactivation ofNeisseria gonorrhoeae: A paradigm changing approach for combating antibiotic-resistant gonococcal infection
Authors: Wang Ying , Ferrer-Espada Raquel , Baglo Yan , Goh Xueping S. , Held Kathryn D. , Grad Yonatan H. , Gu Ying , Gelfand Jeffrey A. , Dai Tianhong 
Published: September 2018

ABSTRACTNeisseria gonorrhoeaeis the causative pathogen of the sexually transmitted disease gonorrhea, a disease at risk of becoming untreatable due to increasing antibiotic resistance. There is a critical need for the development of new anti-gonococcal therapies. In this study, we investigated the effectiveness of antimicrobial blue light (aBL), an innovative non-antibiotic approach, for the inactivation of antibiotic-resistantN.gonorrhoeae. Our findings indicated that aBL at 405 nm preferentially inactivated antibiotic-resistantN. gonorrhoeaeover the vaginal epithelial cells. Furthermore, no genotoxicity of aBL to the vaginal epithelial cells was observed at the exposure for inactivatingN. gonorrhoeae. aBL also effectively inactivatedN. gonorrhoeaethat had invaded into the vaginal epithelial cells. No gonococcal resistance to aBL developed after 15 successive cycles of sub-therapeutic inactivation. Endogenous aBL-active photosensitizing chromophores (porphyrins and flavins) inN. gonorrhoeaewere identified and quantified using ultra performance liquid chromatography, with coproporphyrin being the most abundant endogenous porphyrin species. Taken together, aBL at 405 nm represents a potent potential treatment for gonococcal infections.One Sentence SummaryaBL selectively inactivated antibiotic-resistantNeisseria gonorrhoeaenover normal vaginal epithelial cells.
The essential role of hypermutation in rapid adaptation to antibiotic stress
Authors: Mehta Heer H. , Prater Amy G. , Beabout Kathryn , Elworth Ryan A. L. , Karavis Mark , Gibbons Henry S. , Shamoo Yousif 
Published: September 2018

AbstractA common outcome of antibiotic exposure in patients andin vitrois the evolution of a hypermutator phenotype that enables rapid adaptation by pathogens. While hypermutation is a robust mechanism for rapid adaptation, it requires trade-offs between the adaptive mutations and the more common “hitchhiker” mutations that accumulate from the increased mutation rate. Using quantitative experimental evolution, we examined the role of hypermutation in driving adaptation ofPseudomonas aeruginosato colistin. Metagenomic deep sequencing revealed 2,657 mutations at>5% frequency in 1,197 genes and 761 mutations in 29 end point isolates. By combining genomic information, phylogenetic analyses, and statistical tests, we showed that evolutionary trajectories leading to resistance could be reliably discerned. In addition to known alleles such aspmrB,hypermutation allowed identification of additional adaptive alleles with epistatic relationships. Although hypermutation provided a short-term fitness benefit, it was detrimental to overall fitness. Alarmingly, a small fraction of the colistin adapted population remained colistin susceptible and escaped hypermutation. In a clinical population, such cells could play a role in re-establishing infection upon withdrawal of colistin. We present here a framework for evaluating the complex evolutionary trajectories of hypermutators that applies to both current and emerging pathogen populations.ImportanceBacteria can increase mutation rates in response to stress as an evolutionary strategy to avoid extinction. However, the complex mutational landscape of hypermutators makes it difficult to distinguish truly adaptive mutations from hitchhikers that follow similar evolutionary trajectories. We provide a framework for evaluating the complex evolutionary trajectories of hypermutators that can be applied to both current and emerging pathogen populations. UsingPseudomonas aeruginosaevolving to colistin as a model system, we examine the essential role of hypermutation in the evolution of resistance. Additionally, our results highlight the presence of a subset of cells that survive and remain susceptible during colistin exposure which can serve as a reservoir for re-infection upon withdrawal of the drug in clinical infections. This study provides a broad understanding of hypermutation during adaptation and describes a series of analyses that will be useful in identifying adaptive mutations in well annotated and novel bacterial mutator populations.
Nearly unbiased estimator of adult population size based on within-cohort half-sibling pairs incorporating flexible reproductive variation
Authors: Akita Tetsuya 
Published: September 2018

AbstractClose-kin mark-recapture (CKMR) is a kinship-based method for estimating adult abundance. However, the application of CKMR is limited to using a kinship relationship that is not affected by family-correlated survivorship, which leads to a biased estimation. We developed a nearly unbiased estimator of the number of mothers in a population, which is based on the known maternal half-sibling relationship found within the same cohort. Our method allowed for variance of the averaged offspring number per mother (between-age variation) and for variance of the offspring number among mothers with the same reproductive potential (within-age variation). Estimators of its variance and coefficient variation were also provided. The performance of the estimators was quantitatively evaluated by running an individual-based model. Our results provide guidance for (i) a sample size to archive the required accuracy and precision when the order of mother size is available and (ii) a degree of uncertainty regarding the estimated mother size when information about the mother size is not available. Taken together, these findings offer an opportunity to shed light on the usefulness of analysing within-cohort half-sibling pairs and will greatly widen the scope of the CKMR method.
A role for the auxin precursor anthranilic acid in root gravitropism via regulation of PIN-FORMED protein polarity and relocalization in Arabidopsis
Authors: Doyle Siamsa M. , Rigal Adeline , Grones Peter , Karady Michal , Barange Deepak K. , Majda Mateusz , Pařízková Barbora , Karampelias Michael , Zwiewka Marta , Pěnčik Aleš , Almqvist Fredrik , Ljung Karin , Novák Ondřej , Robert Stéphanie 
Published: September 2018

SummaryDistribution of auxin within plant tissues is of great importance for developmental plasticity, including root gravitropic growth. Auxin flow is directed by the subcellular polar distribution and dynamic relocalization of auxin transporters such as the PIN-FORMED (PIN) efflux carriers, which can be influenced by the main natural plant auxin indole-3-acetic acid (IAA). Anthranilic acid (AA) is an important early precursor of IAA and previously published studies with AA analogues suggested that AA may also regulate PIN localization.Using Arabidopsis thaliana as a model species, we studied an AA-deficient mutant displaying agravitropic root growth, treated seedlings with AA and AA analogues and transformed lines to over-produce AA while inhibiting its conversion to downstream IAA precursors.We showed that AA rescues root gravitropic growth in the AA-deficient mutant at concentrations that do not rescue IAA levels. Overproduction of AA affects root gravitropism without affecting IAA levels. Treatments with, or deficiency in, AA result in defects in PIN polarity and gravistimulus-induced PIN relocalization in root cells.Our results reveal a previously unknown role for AA in the regulation of PIN subcellular localization and dynamics involved in root gravitropism, which is independent of its better-known role in IAA biosynthesis.
Transgenerational developmental effects of immune priming in the red flour beetle Tribolium castaneum
Authors: Schulz Nora KE , Sell Marie Pauline , Ferro Kevin , Kleinhölting Nico , Kurtz Joachim 
Published: September 2018

AbstractImmune priming, the increased chance to survive a secondary encounter with a pathogen, has been described for many invertebrate species, which lack the classical adaptive immune system of vertebrates. Priming can be specific even for closely related bacterial strains, last up to the entire lifespan of an individual, and in some species, it can also be transferred to the offspring and is then called transgenerational immune priming (TGIP). In the red flour beetle Tribolium castaneum, a pest of stored grains, TGIP has even been shown to be transferred paternally after injection of adult beetles with heat-killed Bacillus thuringiensis.Here we studied whether TGIP in T. castaneum is also transferred to the second filial generation, whether it can also occur after oral and injection priming of larvae and whether it has effects on offspring development. We found that paternal priming with B. thuringiensis does not only protect the first but also the second offspring generation. Also, fitness costs of the immune priming became apparent, when the first filial generation produced fewer offspring. Furthermore, we used two different routes of exposure to prime larvae, either by injecting them with heat-killed bacteria or orally feeding them B. thuringiensis spore culture supernatant. Neither of the parental larval priming methods led to any direct benefits regarding offspring resistance. However, the injections slowed down development of the injected individuals, while oral priming with both a pathogenic and a non-pathogenic strain of B. thuringiensis delayed offspring development.The long-lasting transgenerational nature of immune priming and its impact on offspring development indicate that potentially underlying epigenetic modifications might be stable over several generations. Therefore, this form of phenotypic plasticity might impact pest control and should be considered when using products of bacterial origin against insects.
High rates of apoptosis visualized in the symbiont-bearing gills of deep-seaBathymodiolusmussels
Authors: Bérénice Piquet , Bruce Shillito , Lallier François H. , Sébastien Duperron , Andersen Ann C. 
Published: September 2018

AbstractSymbiosis betweenBathymodiolusand Gammaproteobacteria enables these deep-sea mussels to live in toxic environments like hydrothermal vents and cold seeps. The quantity of endosymbionts within the gill-bacteriocytes appears to vary according to the hosts environment. We investigated the hypothesis of a control of the endosymbionts density by apoptosis, a programmed cell death. We used fluorometric TUNEL-method and active Caspase-3-targeting antibodies to visualize and quantify apoptotic cells in mussel gills. To avoid artefacts due to depressurization upon specimen recovery from the deep-sea, we compared the apoptotic rates between mussels recovered unpressurised, versus mussels recovered in a pressure-maintaining device, in two species from hydrothermal vents on the Mid-Atlantic Ridge:Bathymodiolus azoricusandB. puteoserpentis.Our results show that pressurized recovery had no significant effect on the apoptotic rate in the gill filaments. Apoptotic levels were highest in the ciliated zone and in the circulating hemocytes, compared to the bacteriocyte zone. Apoptotic gill-cells inB.aff.boomerangfrom the pockmarks off the Gulf of Guinea, show similar distribution patterns. Deep-sea symbiotic mussels have much higher rates of apoptosis in their gills than the coastal musselMytilus eduliswithout chemolithoautotrophic symbionts. We discuss how apoptosis might be one of the mechanisms that contribute to the adaptation of deep-sea mussels to toxic environments and/or to symbiosis.
Computational framework for exploring the interplay of diet and gut microbiota in autism
Authors: Palukuri Meghana Venkata , Shivakumar Shruti , Sahoo Swagatika , Rengaswamy Raghunathan 
Published: September 2018

AbstractAutism spectrum disorder (ASD)1refers to the set of complex neurological disorders characterized by repetitive behaviour. The reported occurrence of abnormal gut bacteria, along with prevalence of gastrointestinal disorders in ASD indicate its strong correlation with the gut microflora. Our study aims to understand the role of diet and gut bacteria in ASD via an integrated constraint-based and PBPK model. Genome scale models of five major gut bacteria, which were reported to be associated with ASD, were integrated with the human host, i.e., the combined small intestinal enterocyte and neuronal brain model. Simultaneously, a permeability-limited two sub compartment PBPK model was developed to determine the distribution of bacteria-derived toxins in the body. The important results include, (i) inclusion of probiotics into the diet of autistic case restores gut balance, majorly seen as a result of reduced oxidative stress in the brain and the gut, (ii) microbiome and diet together mediate host metabolism in autism, majorly via the nucleotide, central carbon, amino acid, and reactive oxygen species metabolisms, and (iii) gut bacterial-specific secretions contribute to autistic metabotype. Thus, the presented integrated model is the first ever quantitative model, providing a mechanistic basis for autism pathogenesis, capturing known biomarkers, as well as, highlighting the potential of novel dietary modifications in alleviating the symptoms of autism.