bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optical coherence tomography as a means to characterize visual pathway involvement in multiple sclerosis
Authors: Wicki Carla A. , Hanson James V.M. , Schippling Sven 
Published: August 2018

Purpose of review
Optical coherence tomography (OCT) is a noninvasive in-vivo imaging tool that enables the quantification of the various retinal layer thicknesses. Given the frequent involvement of the visual pathway in multiple sclerosis, OCT has become an important tool in clinical practice, research and clinical trials. In this review, the role of OCT as a means to investigate visual pathway damage in multiple sclerosis is discussed.

Recent findings
Evidence from recent OCT studies suggests that the peripapillary retinal nerve fibre layer (pRNFL) appears to be an ideal marker of axonal integrity, whereas the macular ganglion cell and inner plexiform layer (GCIP) thickness enables early detection of neuronal degeneration in multiple sclerosis. The thickness of the macular inner nuclear layer (INL) has been suggested as a biomarker for inflammatory disease activity and treatment response in multiple sclerosis. OCT parameters may also be used as an outcome measure in clinical trials evaluating the neuroprotective or regenerative potential of new treatments.

Summary
OCT provides insights into multiple sclerosis beyond the visual pathway. It is capable of quantifying the major pathological hallmarks of the disease, specifically inflammation and neuroaxonal degeneration. OCT, therefore, has the potential to become another mainstay in the monitoring of multiple sclerosis patients.
SciPipe - A workflow library for agile development of complex and dynamic bioinformatics pipelines
Authors: Lampa Samuel , Dahlö Martin , Alvarsson Jonathan , Spjuth Ola 
Published: August 2018

AbstractBackgroundThe complex nature of biological data has driven the development of specialized software tools. Scientific workflow management systems simplify the assembly of such tools into pipelines, assist with job automation and aid reproducibility of analyses. Many contemporary workflow tools are specialized and not designed for highly complex workflows, such as with nested loops, dynamic scheduling and parametriza-tion, which is common in e.g. machine learning.FindingsSciPipe is a workflow programming library implemented in the programming language Go, for managing complex and dynamic pipelines in bioinformatics, cheminformatics and other fields. SciPipe helps in particular with workflow constructs common in machine learning, such as extensive branching, parameter sweeps and dynamic scheduling and parametrization of downstream tasks. SciPipe builds on Flow-based programming principles to support agile development of workflows based on a library of self-contained, reusable components. It supports running subsets of workflows for improved iterative development, and provides a data-centric audit logging feature that saves a full audit trace for every output file of a workflow, which can be converted to other formats such as HTML, TeX and PDF on-demand. The utility of SciPipe is demonstrated with a machine learning pipeline, a genomics, and a transcriptomics pipeline.ConclusionsSciPipe provides a solution for agile development of complex and dynamic pipelines, espe-cially in machine leaning, through a flexible programming API suitable for scientists used to programming or scripting.
Genome-wide repressive capacity of promoter DNA methylation is revealed through epigenomic manipulation
Authors: Korthauer Keegan , Irizarry Rafael A. 
Published: August 2018

AbstractThe scientific community is increasingly embracing open science. This growing commitment to open science should be applauded and encouraged, especially when it occurs voluntarily and prior to peer review. Thanks to other researchers’ dedication to open science, we have had the privilege of conducting a reanalysis of a landmark experiment published as a preprint with data made available in a public repository. The study in question found that promoter DNA methylation is frequently insufficient to induce transcriptional repression, which appears to contradict a large body of observational studies showing a strong association between DNA methylation and gene expression. This study was the first to evaluate whether forcibly methylating thousands of DNA promoter regions is sufficient to suppress gene expression. The authors’ data analysis did not find a strong relationship between promoter methylation and transcriptional repression. However, their analyses did not make full use of statistical inference and applied a normalization technique that removes global differences that are representative of the actual biological system. Here we reanalyze the data with an approach that includes statistical inference of differentially methylated regions, as well as a normalization technique that accounts for global expression differences. We find that forced DNA methylation of thousands of promoters overwhelmingly represses gene expression. In addition, we show that complementary epigenetic marks of active transcription are reduced as a result of DNA methylation. Finally, by studying whether these associations are sensitive to the CG density of promoters, we find no substantial differences in the association between promoters with and without a CG island. The code needed to reproduce are analysis is included in the public GitHub repository github.com/kdkorthauer/repressivecapacity.
Structure mapping of dengue and Zika viruses reveals new functional long-range interactions
Authors: Huber Roland G. , Lim Xin Ni , Ng Wy Ching , Sim Adelene , Poh Hui Xian , Shen Yang , Lim Su Ying , Sundstrom Anna Karin Beatrice , Sun Xuyang , Aw Jong Ghut , Too Horng Khit , Boey Peng Hee , Wilm Andreas , Chawla Tanu , Choy Ming Ju , Jiang Lu , de Sessions Paola Florez , Loh Xian Jun , Alonso Sylvie , Hibberd Martin , Nagarajan Niranjan , Ooi Eng Eong , Bond Peter J. , Sessions October M. , Wan Yue 
Published: August 2018

AbstractDengue and Zika are clinically important members of the Flaviviridae family that utilizes an 11kb positive strand RNA for genome regulation. While structures have been mapped primarily in the UTRs, much remains to be learnt about how the rest of the genome folds to enable function. Here, we performed secondary structure and pair-wise interaction mapping on four dengue serotypes and four Zika strains in their native virus particles and infected cells. Comparative analysis of SHAPE reactivities across serotypes nominated potentially functional regions that are highly structured, show structure conservation, and low synonymous mutation rates, including a structure associated with ribosome pausing. Pair-wise interaction mapping by SPLASH further reveals new pair-wise interactions, in addition to the known circularization sequence. 40% of pair-wise interactions form alternative structures, suggesting extensive structural heterogeneity. Analysis of shared pair-wise interactions between serotypes revealed macro-organization whereby interactions are preserved at their physical locations, beyond their sequence identities. In addition, structure mapping of virus genomes released in solution-as well as inside host cells-showed that other helicases, in addition to the ribosome, play a role in unwinding viral structures inside cells. Mutational experiments that disrupt in cell and in virion pair-wise interactions result in virus attenuation, demonstrating their importance during the virus life-cycle.
Isoform switching as a mechanism of acquired resistance to isocitrate dehydrogenase inhibition
Authors: Harding James J. , Lowery Maeve A. , Shih Alan H. , Schvartzman Juan M. , Hou Shengqi , Famulare Christopher , Patel Minal , Roshal Mikhail , Do Richard K. G. , Zehir Ahmet , You Daoqi , Selcuklu S. Duygu , Viale Agnes , Tallman Martin S. , Hyman David M. , Reznik Ed , Finley Lydia W.S. , Papaemmanuil Elli , Tosolini Alessandra , Frattini Mark G. , MacBeth Kyle J. , Liu Guowen , Fan Bin , Choe Sung , Wu Bin , Janjigian Yelena Y. , Mellinghoff Ingo K. , Diaz Luis A. , Levine Ross L. , Abou-Alfa Ghassan K. , Stein Eytan M. , Intlekofer Andrew M. 
Published: August 2018

AbstractSomatic mutations in cytosolic or mitochondrial isoforms of isocitrate dehydrogenase (IDH1 or IDH2, respectively) contribute to oncogenesis via production of the metabolite 2-hydroxyglutarate (2HG). Isoform-selective IDH inhibitors suppress 2HG production and induce clinical responses in patients with IDH1- and IDH2-mutant malignancies. Despite the promising activity of IDH inhibitors, the mechanisms that mediate resistance to IDH inhibition are poorly understood. Here, we describe four clinical cases that identify mutant IDH isoform switching, either from mutant IDH1 to mutant IDH2 or vice versa, as a mechanism of acquired clinical resistance to IDH inhibition in solid and liquid tumors.SignificanceIDH-mutant cancers can develop resistance to isoform-selective IDH inhibition by “isoform switching” from mutant IDH1 to mutant IDH2 or vice versa, thereby restoring 2-hydroxyglutarate (2HG) production by the tumor. These findings underscore a role for continued 2HG production in tumor progression and suggest therapeutic strategies to prevent or overcome resistance.
Competition between mobile genetic elements drives optimization of a phage-encoded CRISPR-Cas system: Insights from a natural arms-race
Authors: McKitterick Amelia C. , LeGault Kristen N. , Angermeyer Angus , Alam Muniral , Seed Kimberley D. 
Published: August 2018

AbstractCRISPR-Cas systems function as adaptive immune systems by acquiring nucleotide sequences called spacers that mediate sequence-specific defense against competitors. Uniquely, the phage ICP1 encodes a Type I-F CRISPR-Cas system that is deployed to target and overcome PLE, a mobile genetic element with anti-phage activity in Vibrio cholerae. Here, we exploit the arms race between ICP1 and PLE to examine spacer acquisition and interference under laboratory conditions to reconcile findings from wild populations. Natural ICP1 isolates encode multiple spacers directed against PLE, but we find that single spacers do not equally interfere with PLE mobilization. High-throughput sequencing to assay spacer acquisition reveals that ICP1 can also acquire spacers that target the V. cholerae chromosome. We find that targeting the V. cholerae chromosome proximal to PLE is sufficient to block PLE and propose a model in which indirect chromosomal spacers are able to circumvent PLE by Cas2-3-mediated processive degradation of the V. cholerae chromosome before PLE mobilization. Generally, laboratory acquired spacers are much more diverse than the subset of spacers maintained by ICP1 in nature, showing how evolutionary pressures can constrain CRISPR-Cas targeting in ways that are often not appreciated through in vitro analyses.
Skin Lesion Classification Via Combining Deep Learning Features and Clinical Criteria Representations
Authors: Li Xiaoxiao , Wu Junyan , Jiang Hongda , Chen Eric Z. , Dong Xu , Rong Ruichen 
Published: August 2018

AbstractSkin lesion is a severe disease globally. Early detection of melanoma in dermoscopy images significantly increases the survival rate. However, the accurate recognition of skin lesion is extremely challenging manually visualization. Hence, reliable automatic classification of skin lesions is meaningful to improve pathologists’ accuracy and efficiency. In this paper, we proposed a two-stage method to combine deep learning features and clinical criteria representations to address skin lesion automated diagnosis task. Stage 1 - feature encoding: Modified deep convolutional neural networks (CNNs, in this paper, we used Dense201 and Res50) were fine-tuned to extract rich image global features. To avoid hair noisy, we developed a lesion segmentation U-Net to mask out the decisive regions and used the masked image as CNNs inputs. In addition, color features, texture features and morphological features were exacted based on clinical criteria; Stage 2 - features fusion: LightGBM was used to select the salient features and model parameters, predicting diagnosis confidence for each category. The proposed deep learning frameworks were evaluated on the ISIC 2018 dataset. Experimental results show the promising accuracies of our frameworks were achieved.
Single-cell RNA-seq reveals distinct dynamic behavior of sex chromosomes during early human embryogenesis
Authors: Zhou Qing , Wang Taifu , Leng Lizhi , Zheng Wei , Huang Jinrong , Fang Fang , Yang Ling , Wang Jian , Yang Huanming , Chen Fang , Lin Ge , Wang Wen-Jing , Kristiansen Karsten 
Published: August 2018

AbstractBackgroundSeveral animal and human studies have demonstrated that sex affects kinetics and metabolism during early embryo development. However, the mechanism governing these differences at the molecular level is unknown, warranting a systematic profiling of gene expression in males and females during embryogenesis.FindingsWe performed comprehensive analyses of gene expression comparing male and female embryos using available single-cell RNA-sequencing data of 1607 individual cells from 99 human preimplantation embryos, covering development stages from 4-cell to late blastocyst (E2 to E7). Consistent chromosome-wide transcription of autosomes was observed, while sex chromosomes showed significant differences after embryonic genome activation (EGA). Differentially expressed genes (DE genes) in male and female embryos mainly involved in the cell cycle, protein translation and metabolism. The Y chromosome was initially activated by pioneer genes, RPS4Y1 and DDX3Y, while the two X chromosomes in female were widely activated after EGA. Expression of X-linked genes in female significantly declined at the late blastocyst stage, especially in trophectoderm cells, revealing a rapid process of dosage compensation.ConclusionsWe observed imbalanced expression from sex chromosomes in male and female embryos during EGA, with dosage compensation occurring first in female trophectoderm cells. Studying the effect of sex differences during human embryogenesis, as well as understanding the mechanism of X chromosome inactivation and its correlation with early miscarriage, will provide a basis for advancing assisted reproductive technology (ART) and thereby improve the treatment of infertility and possibly enhance reproductive health.
Demographic inference using a particle filter for continuous Markov Jump processes
Authors: Henderson Donna , Zhu Sha (Joe) , Cole Chris , Lunter Gerton 
Published: August 2018

AbstractDemographic events shape a population’s genetic diversity, a process described by the coalescent-with-recombination (CwR) model that relates demography and genetics by an unobserved sequence of genealogies. The space of genealogies over genomes is large and complex, making inference under this model challenging.We approximate the CwR with a continuous-time and -space Markov jump process. We develop a particle filter for such processes, using way-points to reduce the problem to the discrete-time case, and generalising the Auxiliary Particle Filter for discrete-time models. We use Variational Bayes for parameter inference to model the uncertainty in parameter estimates for rare events, avoiding biases seen with Expectation Maximization.Using real and simulated genomes, we show that past population sizes can be accurately inferred over a larger range of epochs than was previously possible, opening the possibility of jointly analyzing multiple genomes under complex demographic models.Code is available athttps://github.com/luntergroup/smcsmcMSC 2010 subject classificationsPrimary 60G55, 62M05, 62M20, 62F15; secondary 92D25.
Emergence and features of the multipartite genome structure of the family Burkholderiaceae revealed through comparative and evolutionary genomics
Authors: diCenzo George C , Mengoni Alessio , Perrin Elena 
Published: August 2018

ABSTRACTThe multipartite genome structure is found in a diverse group of important symbiotic and pathogenic bacteria; however, the advantage of this genome structure remains incompletely understood. Here, we perform comparative genomics of hundreds of finished β-proteobacterial genomes to study the role and emergence of multipartite genomes. Nearly all essential secondary replicons (chromids) of the β-proteobacteria are found in the family Burkholderiaceae. These replicons arose from just two plasmid acquisition events, and they were likely stabilized early in their evolution by the presence of core genes, at least some of which were likely acquired through an inter-replicon translocation event. On average, Burkholderiaceae genera with multipartite genomes had a larger total genome size, but smaller chromosome, than genera without secondary replicons. Pangenome-level functional enrichment analyses suggested that inter-replicon functional biases are partially driven by the enrichment of secondary replicons in the accessory pangenome fraction. Nevertheless, the small overlap in orthologous groups present in each replicon’s pangenome indicates a clear functional separation of the replicons. Chromids appeared biased to environmental adaptation, as the functional categories enriched on chromids were also over-represented on the chromosomes of the environmental genera (Paraburkholderia, Cupriavidus) compared to the pathogenic genera (Burkholderia, Ralstonia). Using ancestral state reconstruction, it was predicted that the rate of accumulation of modern-day genes by chromids was more rapid than the rate of gene accumulation by the chromosomes. Overall, the data are consistent with a model where the primary advantage of secondary replicons is in facilitating increased rates of gene acquisition through horizontal gene transfer, consequently resulting in a replicon enriched in genes associated with adaptation to novel environments.
Climate Resilience Index as a tool to explore households’ resilience to climate change-induced shocks in Dinki watershed, central highlands of Ethiopia Households’ resilience to climate change impacts
Authors: Asmamaw Mengistu , Ambelu Argaw , Mereta Seid Tiku 
Published: August 2018

AbstractThis study assessed households’ resilience to climate change-induced shocks in Dinki watershed, northcentral highlands of Ethiopia. The data were collected through cross-sectional survey conducted on 288 households, six focus group discussions and 15 key informant interviews. The Climate Resilience Index (CRI) and the Livelihood Resilience Index (LRI) based on the three-resilience capacities (3Ds) frame, using absorptive, adaptive and transformative, were used to measure households’ resilience to climate change-induced shocks on agro-ecological unit of analysis. Findings indicate that the CRI and the resilience capacities based on the indexed scores of major components clearly differentiated the study communities in terms of their agro-ecological zones. Specifically, the LRI score showed that absorptive capacity (0.495) was the leading contributing factor to resilience followed by adaptive (0.449) and transformative (0.387) capacities. Likewise, the midland was relatively more resilient with a mean index value of 0.461. The study showed that access to and use of livelihood resources, such as farmlands and livestock holdings, diversity of income sources, infrastructure and social capital were determinants of households’ resilience. In general, it might be due to their exposure to recurrent shocks coupled with limited adaptive capacities including underdeveloped public services, poor livelihood diversification practices, among others, the study communities showed minimal resilience capacity with a mean score of 0.44. Thus, in addition to short-term buffering strategies, intervention priority focusing on both adaptive and transformative capacities, particularly focusing on most vulnerable localities and constrained livelihood strategies, would contribute to ensure long-term resilience in the study communities.
A standardised framework to identify optimal animal models for efficacy assessment in drug development
Authors: Ferreira Guilherme S. , Veening-Griffioen Désirée , Boon Wouter , Moors Ellen , Wied Christine Gispen-de , Schellekens Huub , van Meer Peter 
Published: August 2018

AbstractIntroductionPoor translation of efficacy data derived from animal models is a potential contributor to costly and unnecessary attrition in clinical trials.ObjectivesTo develop a tool to assess, validate and compare the clinical translatability of animal models used for the preliminary assessment of efficacy.Design and ResultsWe conducted an exploratory literature search to identify the key aspects to validate animal models. Eight aspects (Epidemiology, Pathophysiology, Genetic, Biochemistry, Aetiology, Histology, Pharmacology and Endpoints) were identified for which questions were drafted to evaluate the different faces of the human disease simulation. Features of the framework include standardised instructions, a weighting and scoring system to compare models as well as contextualising factors regarding model similarity and evidence uncertainty. We included a quality assessment of the internal validity of drug intervention studies included in the Pharmacological validation section for both effective and ineffective drugs in humans. A web-based survey was conducted with experts from different stakeholders to gather input on the framework. Finally, we present a case study of a preliminary validation and comparison of two animal models for Duchenne Muscular Dystrophy (mdx mouse and GRMD dog) and Diabetes Type 2 (ZDF rat and db/db mouse). We show that there are significant differences between the mdx mouse and the GRMD dog, the latter mimicking the human condition to a greater extent than the mouse despite the considerable lack of published data. In DT2, both the ZDF rat and the db/db mouse are comparable with minor differences in pathophysiology.ConclusionsFIMD facilitates drug development by serving as the basis to select the most relevant model that can provide meaningful and translatable results to progress drug candidates to the clinic.
Inhibitory muscarinic acetylcholine receptors enhance aversive olfactory conditioning in adult Drosophila
Authors: Bielopolski Noa , Amin Hoger , Apostolopoulou Anthi A. , Rozenfeld Eyal , Lerner Hadas , Huetteroth Wolf , Lin Andrew C. , Parnas Moshe 
Published: August 2018

AbstractOlfactory associative learning inDrosophilais mediated by synaptic plasticity between the Kenyon cells of the mushroom body and their output neurons. Both Kenyon cells and their inputs are cholinergic, yet little is known about the physiological function of muscarinic acetylcholine receptors in learning in adult flies. Here we show that aversive olfactory learning in adult flies requires type A muscarinic acetylcholine receptors (mAChR-A) specifically in the gamma subtype of Kenyon cells. Surprisingly, mAChR-A inhibits odor responses in both Kenyon cell dendrites and axons. Moreover, mAChR-A knockdown impairs the learning-associated depression of odor responses in a mushroom body output neuron. Our results suggest that mAChR-A is required at Kenyon cell presynaptic terminals to depress the synapses between Kenyon cells and their output neurons, and may suggest a role for the recently discovered axo-axonal synapses between Kenyon cells.