bluuebunny/crossref_metadata_2025 huggingface dataset:
Normative Data of the Interorbital Distance in Thai Population
Authors: Chatdokmaiprai Chalermpong , Kiranantawat Kidakorn , Lertsithichai Panuwat , Taeshineetanakul Patamintita
Published: September 2018

The incidence of the patients with craniofacial anomalies was high in southeast-Asian countries, for example, fronto-ethmoidal encephalo-menigocele or craniosynostosis. These craniofacial anomalies usually involve orbits, so a surgical orbital reconstruction is always required.

Various methods have been used in the past to indirectly analyze the craniofacial region. Plain skull radiography, anthropometry, and cephalometry provided the limited information of interorbital distance in terms of accuracy whereas the interorbital distance is crucial to be reconstructed, increasing or decreasing. The accurate normal interorbital distance which grows by age as other craniofacial structures is the important data in the part of interorbital and orbital reconstruction. To date, the normative data of the bony interorbital distance among Thai population have not been established.

The purpose of this study is to provide normal values and the growth patterns of the bony interorbital distances and other dimensions of the orbit according to age among Thai population through the axial computed tomography. Comparisons can then be made between normal values and those for an individual patient or those for a group of patients, for example, those with front-ethmoidal meningoencephalocele, Crouzon, or Treacher–Collins syndrome, or among values for individual patients at different time intervals.

A retrospective study of computed tomography (CT) scan series of 698 normal orbits from 349 skeletally normal subjects (202 men and 147 women) was enrolled. The age range of the patients was 0 to 21 years (mean, 10.2 years; SD, 5.8 years). A series of 12 measurements were obtained from the CT scans of each subject. All CT images were obtained from patients who underwent CT of the facial bone, brain, and orbits at the Department of Radiology of 3 big hospital in Bangkok–Ramathibodi, Samitivej Srinakarin, and Bangkok hospital–since 2010 to 2015.

The normal measurement values in the orbital region through the CT images, as the normal periorbital growth curve, will help improving diagnostic accuracy, staging of reconstruction, precision of corrective surgery, and follow-up of the Thai patients with craniofacial abnormalities such as front-ethmoidal meningoencephalocele, hypertelorism. These data may also apply to the related population in the southeast-Asian countries.
The ATP-dependent chromatin remodelling enzyme Uls1 prevents Topoisomerase II poisoning
Authors: Swanston Amy , Zabrady Katerina , Ferreira Helder C.
Published: September 2018

Topoisomerase II (Top2) is an essential enzyme that decatenates DNA via a transient Top2-DNA covalent intermediate. This intermediate can be stabilised by a class of drugs termed Top2 poisons, resulting in massive DNA damage. Thus, Top2 activity is a double-edged sword that needs to be carefully controlled to maintain genome stability. We show that Uls1, an ATP-dependent chromatin remodelling (Snf2) enzyme, can alter Top2 chromatin binding and prevent Top2 poisoning in yeast. Deletion mutants ofULS1are hypersensitive to the Top2 poison acriflavine (ACF), activating the DNA damage checkpoint. We map Uls1’s Top2 interaction domain and show that this, together with its ATPase activity, is essential for Uls1 function. By performing ChIP-seq, we show that ACF leads to a general increase in Top2 binding across the genome. We map Uls1 binding sites and identify tRNA genes as key regions where Uls1 associates after ACF treatment. Importantly, the presence of Uls1 at these sites prevents ACF-dependent Top2 accumulation. Our data reveal the effect of Top2 poisons on the global Top2 binding landscape and highlights the role of Uls1 in antagonising Top2 function. Remodelling Top2 binding is thus an important new means by which Snf2 enzymes promote genome stability.
Pan-cancer whole genome analyses of metastatic solid tumors
Authors: Priestley Peter , Baber Jonathan , Lolkema Martijn P. , Steeghs Neeltje , de Bruijn Ewart , Shale Charles , Duyvesteyn Korneel , Haidari Susan , van Hoeck Arne , Onstenk Wendy , Roepman Paul , Voda Mircea , Bloemendal Haiko J. , Tjan-Heijnen Vivianne C.G. , van Herpen Carla M.L. , Labots Mariette , Witteveen Petronella O. , Smit Egbert F. , Sleijfer Stefan , Voest Emile E. , Cuppen Edwin
Published: September 2018

Metastatic cancer is one of the major causes of death and is associated with poor treatment efficiency. A better understanding of the characteristics of late stage cancer is required to help tailor personalised treatment, reduce overtreatment and improve outcomes. Here we describe the largest pan-cancer study of metastatic solid tumor genomes, including 2,520 whole genome-sequenced tumor-normal pairs, analyzed at a median depth of 106x and 38x respectively, and surveying over 70 million somatic variants. Metastatic lesions were found to be very diverse, with mutation characteristics reflecting those of the primary tumor types, although with high rates of whole genome duplication events (56%). Metastatic lesions are relatively homogeneous with the vast majority (96%) of driver mutations being clonal and up to 80% of tumor suppressor genes bi-allelically inactivated through different mutational mechanisms. For 62% of all patients, genetic variants that may be associated with outcome of approved or experimental therapies were detected. These actionable events were distributed across various mutation types underlining the importance of comprehensive genomic tumor profiling for cancer precision medicine.
Evaluation of correlates of protection against influenza A(H3N2) and A(H1N1)pdm09 infection: Applications to the hospitalized patient population
Authors: Petrie Joshua G. , Martin Emily T. , Truscon Rachel , Johnson Emileigh , Cheng Caroline K. , McSpadden EJ , Malosh Ryan E. , Lauring Adam S. , Lamerato Lois E. , Eichelberger Maryna C. , Ferdinands Jill M. , Monto Arnold S.
Published: September 2018

Background

Influenza vaccines are important for prevention of influenza-associated hospitalization. Assessments of serologic correlates of protection can support interpretation of influenza vaccine effectiveness evaluations in hospitalized populations.

Methods

Serum specimens collected at admission from adults hospitalized for treatment of acute respiratory illnesses during two influenza seasons were tested in hemagglutination-inhibition (HAI) and neuraminidase-inhibition (NAI) assays. We evaluated the suitability of these specimens as proxies for pre-infection immune status, and measured associations between antibody titers and influenza vaccination and infection

Results

Specimens were collected within 3 days of illness onset from 65% of participants; geometric mean titers (GMTs) did not vary by day of collection. In both seasons, vaccinated participants had higher HAI and NAI GMTs than unvaccinated participants. HAI titers against the 2014-2015 A(H3N2) vaccine strain did not correlate with protection from infection with antigenically-drifted A(H3N2) viruses that circulated that season. In contrast, higher HAI titers against the A(H1N1)pdm09 vaccine strain were associated with reduced odds of A(H1N1)pdm09 infection in 2015-2016.

Conclusions

Serum collected after hospital admission can be used to assess correlates of protection against influenza infection. Broader implementation of similar studies would provide an opportunity to understand the successes and shortcomings of current influenza vaccines.
Predictive Modelling of The Dynamic Patterns of Thinking in Attention-Deficit/Hyperactivity Disorder: Diagnostic Accuracy of Spatiotemporal Fractal Measures
Authors: Labra-Spröhnle F. , Smith G. , Ahammer H. , Postlethwaite C. , Liu I. , Teesdale-Spittle P. , Frean M.
Published: September 2018

Background

Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental condition characterized by executive function (EF) dynamics disturbances. Notwithstanding, current advances in translational neuroscience, no ADHD objective, clinically useful, diagnostic marker is available to date.

Objectives

Using a customized definition of EF and a new clinical paradigm, we performed a prospective diagnostic accuracy trial to assess the diagnostic value of several fractal measures from the thinking processes or inferences in a cohort of ADHD children and typically developing controls.

Method

We included children from age five to twelve diagnosed with a reference standard based on case history, physical and neurological examination, Conners 3rdEdition, and DSM-V™. The index test consisted of a computer-based inference task with a set of eight different instances of the “Battleships” game to be solved. A consecutive series of 18 cases and 18 controls (n = 36) recruited at the primary paediatrics service from the Nelson Marlborough Health in New Zealand underwent the reference standard and the index test. Several fractal measures were obtained from the inference task to produce supervised classification models.

Results

Notably, the summarized logistic regression’s predicted probabilities from the eight games played by each children yielded a 100% classification accuracy, sensitivity and specificity in both a training and an independent testing/validating cohort.

Conclusions

From a translational vantage point the expeditious method and the robust results make this technique a promising candidate to develop a screening, diagnostic and monitoring system for ADHD, and may serve to assess other EF disturbances.
Genome-wide active enhancer identification using cell type-specific signatures of epigenomic activity
Authors: Jhanwar Shalu , Ossowski Stephan , Davila-Velderrain Jose
Published: September 2018

Recently enhancers have emerged as key players regulating crucial mechanisms such as cell fate determination and establishment of spatiotemporal patterns of gene expression during development. Due to their functional and structural complexity, an accurate in silico identification of active enhancers under specific conditions remain challenging. We present a novel machine learning based method that derives epigenomic patterns exclusively from experimentally characterized active enhancers contrasted with a weighted set of non-enhancer genomic regions. We demonstrate better predictive performance over previous methods, as well as wide generalizability by identifying and annotating active enhancers genome-wide across different tissues/cell types in human and mouse.
Dissecting heterogeneous cell populations across drug and disease conditions with PopAlign
Authors: Chen Sisi , Park Jong H. , Tsou Tiffany , Rivaud Paul , Charles Emeric , Haliburton John , Pichiorri Flavia , Thomson Matt
Published: September 2018

Single-cell measurement techniques can now probe gene expression in heterogeneous cell populations from the human body across a range of environmental and physiological conditions. However, new mathematical and computational methods are required to represent and analyze gene expression changes that occur in complex mixtures of single cells as they respond to signals, drugs, or disease states. Here, we introduce a mathematical modeling platform, PopAlign, that automatically identifies subpopulations of cells within a heterogeneous mixture, and tracks gene expression and cell abundance changes across subpopulations by constructing and comparing probabilistic models. Probabilistic models provide a low-error, compressed representation of single cell data that enables efficient large-scale computations. We apply PopAlign to analyze the impact of 40 different immunomodulatory compounds on a heterogeneous population of donor-derived human immune cells as well as patient-specific disease signatures in multiple myeloma. PopAlign scales to comparisons involving tens to hundreds of samples, enabling large-scale studies of natural and engineered cell populations as they respond to drugs, signals or physiological change.
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

Introduction

Malawi 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.

Methods

We 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.

Results

An 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).

Conclusions

Risk 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

Displacement-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

Intergenerational 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

Standing 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

Background

Somatic 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).

Results

In 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.

Conclusion

Our 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

Cancer 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

Neisseria 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 Summary

aBL 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

A 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.

Importance

Bacteria 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

Close-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

Distribution 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

Immune 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.
Comparison of Efficiency and Specificity of CRISPR-Associated (Cas) Nucleases in Plants: An Expanded Toolkit for Precision Genome Engineering
Authors: Raitskin Oleg , Schudoma Christian , West Anthony , Patron Nicola J.
Published: September 2018

Molecular tools adapted from bacterial CRISPR (Clustered Regulatory Interspaced Short Palindromic Repeats) systems for adaptive immunity have become widely used for plant genome engineering, both to investigate gene functions and to engineer desirable traits. A number of different Cas (CRISPR-associated) nucleases are now used but, as most studies performed to date have engineered different targets using a variety of plant species and molecular tools, it has been difficult to draw conclusions about the comparative performance of different nucleases. Due to the time and effort required to regenerate engineered plants, efficiency is critical. In addition, there have been several reports of mutations at sequences with less than perfect identity to the target. While in some plant species it is possible to remove these so-called ‘off-targets’ by backcrossing to a parental line, the specificity of genome engineering tools is important when targeting specific members of closely-related gene families, especially when recent paralogues are co-located in the genome and unlikely to segregate. Specificity is also important for species that take years to reach sexual maturity or that are clonally propagated. Here, we directly compare the efficiency and specificity of Cas nucleases from different bacterial species together with engineered variants of Cas9. We find that the nucleotide content correlates with efficiency and that Cas9 from Staphylococcus aureus is comparatively most efficient at inducing mutations. We also demonstrate that ‘high-fidelity’ variants of Cas9 can reduce off-target mutations in plants. We present these molecular tools as standardised DNA parts to facilitate their re-use.
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

Symbiosis 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

Autism 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.
No clear monogenic links between left-handedness and situs inversus
Authors: Postema Merel C. , Carrion-Castillo Amaia , Fisher Simon E. , Vingerhoets Guy , Francks Clyde
Published: September 2018

Left-handedness is a complex trait which might sometimes involve rare, monogenic contributions. Situs inversus (SI) of the visceral organs can occur with Primary Ciliary Dyskinesia (PCD), due to mutations which affect left-right axis formation. Roughly 10% of people with SI and PCD are left-handed, similar to the general population. However, in non-PCD SI, the rate of left-handedness may be elevated. We sequenced the genomes of nine non-PCD SI people who show an elevated rate of left-handedness (five out of nine). We also sequenced six SI people with PCD as positive controls, and fifteen unaffected people as technical controls. Recessive mutations in known PCD genes were found in all positive controls with PCD. Of the nine non-PCD SI cases, two had recessive mutations in known PCD genes, suggesting reduced penetrance for PCD, and one had a recessive mutation in the non-PCD laterality gene PKD1L1. However, six of the nine non-PCD SI cases, including most of the left-handers, had no mutations in likely candidate genes, nor any significant biological pathways affected by their mutations. Therefore we did not identify a molecular link between visceral and brain laterality. While we cannot exclude a monogenic basis for non-PCD SI with left-handedness, multifactorial and non-genetic models must also be considered.
Unbiased screen of RNA tailing enzymes at single-nucleotide resolution reveals a poly(UG) polymerase required for genome integrity and RNA silencing
Authors: Preston Melanie A. , Porter Douglas F. , Chen Fan , Buter Natascha , Lapointe Christopher P. , Keles Sunduz , Kimble Judith , Wickens Marvin
Published: September 2018

Ribonucleotidyl transferases (rNTases) add non-templated ribonucleotides to diverse RNAs. We developed a screening strategy inS. cerevisiaeto identify sequences added by candidate enzymes from different organisms at single-nucleotide resolution. The rNTase activities of 19 previously unexplored enzymes were determined. In addition to poly(A)- and poly(U)-adding enzymes, we identified a C-adding enzyme that is likely part of a two-enzyme system that adds CCA to tRNAs in a eukaryote; a nucleotidyl transferase that adds nucleotides to RNA without apparent nucleotide preference; and a poly(UG) polymerase,C. elegansMUT-2, which adds alternating U and G nucleotides to form poly(UG) tails. MUT-2 is known to be required for certain forms of RNA silencing, and mutations in the enzyme that are defective in silencing also fail to add poly(UG) tails in our assay. We propose that MUT-2 poly(UG) polymerase activity is required to promote genome integrity and RNA silencing.
Short exon prediction based on multiscale products of a genomic-inspired multiscale bilateral filtering
Authors: Zhang Xiaolei , Pan Weijun
Published: September 2018

Multiscale signal processing techniques such as wavelet filtering have proved to be particularly successful in predicting exon sequences. Traditional wavelet predictor is domain filtering, and enforces exon features by weighting nucleotide values with coefficients. Such a measure performs linear filtering and is not suitable for preserving the short coding exons and the exon-intron boundaries. This paper describes a short exon prediction framework that is capable of non-linearly processing DNA sequences while achieving high prediction rates. There are two key contributions. The first is the introduction of a genomic-inspired multiscale bilateral filtering (MSBF) which exploits both weighting coefficients in the spatial domain and nucleotide similarity in the range. Similarly to wavelet transform, the MSBF is also defined as a weighted sum of nucleotides. The difference is that the MSBF takes into account the variation of nucleotides at a specific codon position. The second contribution is the exploitation of inter-scale correlation in MSBF domain to find the inter-scale dependency on the differences between the exon signal and the background noise. This favourite property is used to sharp the important structures while weakening noise. Three benchmark data sets have been used in the evaluation of considered methods. By comparison with two existing techniques, the prediction results demonstrate that: the proposed method reveals at least improvement of 50.5%, 36.7%, 12.8%, 17.8%, 17.7%, 11.5% and 12.2% on the exons length of 1-49, 50-74, 75-99, 100-124, 125-149, 150-174 and 175-199, respectively. The MSBF of its nonlinear nature is good at energy compaction, which makes it capable of locating the sharp variations around short exons. The direct scale multiplication of coefficients at several adjacent scales obviously enhanced exon features while the noise contents were suppressed. We show that the non-linear nature and correlation-based property achieved in proposed predictor is greater than that for traditional filtering, which leads to better exon prediction performance. There are some possible applications of this predictor. Its good localization and protection of sharp variations will make the predictor be suitable to perform fault diagnosis of aero-engine.
Estimating the current burden of Chagas disease in Mexico: a systematic review of epidemiological surveys from 2006 to 2017
Authors: Arnal Audrey , Waleckx Etienne , Herrera Claudia , Dumonteil Eric
Published: September 2018

Background

In Mexico, estimates of Chagas disease prevalence and burden vary widely. Updating surveillance data is therefore an important priority to ensure that Chagas disease does not remain a barrier to the development of Mexico’s most vulnerable populations.

Methodology/Principal Findings

The aim of this systematic review was to analyze the literature on epidemiological surveys to estimate Chagas disease prevalence and burden in Mexico, during the period 2006 to 2017. A total of 2,764 articles were screened and 38 were retained for the final analysis. Epidemiological surveys have been performed in most of Mexico, but with variable geographic coverage. Based on studies reporting confirmed cases, i.e. using at least 2 serological tests, the national seroprevalence of Trypanosoma cruzi infection was 2.26% [95% Confidence Interval (CI) 2.12-2.41], suggesting that there are 2.71 million cases in Mexico. Studies focused on pregnant women, which may transmit the parasite to their newborn during pregnancy, reported a seroprevalence of 1.00% [95% CI 0.87-1.14], suggesting that there are 22,930 births from T. cruzi infected pregnant women per year, and 1,445 cases of congenitally infected newborns per year. Children under 18 years had a seropositivity rate of 1.49% [95% CI 1.20-1.85], which indicate ongoing transmission. Finally, cases of T. cruzi infection in blood donors have also been reported in most states, with a national seroprevalence of 0.51% [95% CI 0.49-0.53].

Conclusions/Significance

Our analysis suggests a disease burden for T. cruzi infection higher than previously recognized, highlighting the urgency of establishing Chagas disease surveillance and control as a key national public health priority in Mexico, to ensure that it does not remain a major barrier to the economic and social development of the country’s most vulnerable populations.

Author summary

In Mexico, estimates of Chagas disease prevalence and burden vary widely due to the ecology and epidemiology of this disease resulting of many geographical, ecological, biological, and social interactions. Better data are thus urgently needed to help develop appropriate public health programs for disease control and patient care. In this study we analyzed published data on T. cruzi seroprevalence infection in Mexico between 2006 and 2017. This systematic review shows a national seroprevalence of T. cruzi infection of 2.26% [95%CI 2.12-2.41], with over 2.71 million cases in Mexico, which is higher than previously recognized. The presence of T. cruzi infection in specific subpopulations such as pregnant women, children and blood donors also informs on specific risks of infection and call for the implementation of well-established control interventions. This work confirms the place of Mexico as the country with the largest number of cases, highlighting the urgency of establishing Chagas disease control as a key national public health priority.