bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuropilin-1/CD304 Expression by Flow Cytometry in Pediatric Precursor B-Acute Lymphoblastic Leukemia: A Minimal Residual Disease and Potential Prognostic Marker
Authors: Abaza Hala M. , Alfeky Mervat A.A. , Eissa Deena S. , Abdel Fattah Mona F. , Annaka Laila M. , Ebeid Fatma S.
Published: December 2017

Flow cytometry (FCM) is used for quantification of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL) through discriminating leukemic B-lymphoblasts from normal B-cell precursor counterparts “hematogones.” Neuropilin-1 (NRP-1)/CD304 is a vascular endothelial growth factor receptor implicated in the progression of hematological malignancies. We evaluated NRP-1/CD304 as MRD and prognostic marker in pediatric precursor B-ALL using FCM. Seventy children with precursor B-ALL and 40 control children were enrolled. CD304 percentage and fluorescence intensity were significantly higher in precursor B-ALL at diagnosis compared with controls. In total, 28 of 70 (40%) precursor B-ALL patients at diagnosis were CD304+ (group A), whereas 42/70 (60%) patients were CD304− (group B). Group A showed higher incidence of lymphadenopathy and TEL-AML1 fusion gene than group B. CD304 was reevaluated in group A patients at day 28 postinduction chemotherapy which revealed 12/28 (42.9%) patients with persistent CD304+ expression (MRD+; group A1) and 16/28 (57.1%) patients who turned CD304− (MRD−; group A2). At diagnosis, group A1 showed lower incidence of TEL-AML1 fusion gene and higher risk stratification than group A2. NRP-1/CD304 expression by FCM is efficient in discriminating leukemic B-lymphoblasts from hematogones, a stable leukemia-associated phenotype for MRD monitoring, and a putative poor prognostic marker in pediatric precursor B-ALL.
New thinking on gonorrhoea control in MSM: are antiseptic mouthwashes the answer?
Authors: Fairley Christopher K. , Zhang Lei , Chow Eric P.F.
Published: November 2017

Purpose of review

The rate of gonorrhoea is rising and is much higher in men who have sex with men (MSM) than heterosexuals. The purpose of this review was to describe research supporting a new paradigm of transmission of gonorrhoea in MSM and interventions that may result from this.

Recent findings

Evidence is accumulating that gonorrhoea in MSM is transmitted differently than previously thought and that asymptomatic sites of infection may play a major role in the persistent of gonorrhoea at a population level. Saliva commonly contains gonorrhoea, and saliva is commonly used during sexual acts. Both in-vitro, in-vivo studies have suggested that antibacterial mouthwash may reduce gonorrhoea at the oropharynx. A recently published mathematical model also suggests that if mouthwash were effective, it would result in considerable declines in the community prevalence in MSM.

A newly suggested paradigm for the transmission of gonorrhoea in MSM could potentially offer a simple condom-free control strategy. But considerable more research is required before it could be recommended even if it were shown to be effective in a clinical trial.
Transition to survivorship: can there be improvement?
Authors: Fitch Margaret I.
Published: November 2017

Purpose of review

The transition from primary cancer treatment to posttreatment follow-up care is seen as critical to the long-term health of survivors. However, relatively little attention has been paid to understanding this pivotal period. This review will offer a brief outline of the significant work surrounding this pivotal time published in the past year.

Recent findings

The growing number of cancer survivors has stimulated an emphasis on finding new models of care, whereby responsibility for survivorship follow-up is transitioned to primary care providers. A variety of models and tools have emerged for follow-up care. Survivorship care plans are heralded as a key component of survivorship care and a vehicle for supporting transition. Uptake of survivorship care plans and implementation of evidence-based models of survivorship care has been slow, hindered by a range of barriers.

Evaluation is needed regarding survivorship models in terms of feasibility, survivor friendliness, cost effectiveness, and achievement of sustainable outcomes. How, and when, to introduce plans for transition to the patient and determine transition readiness are important considerations but need to be informed by evidence. Additional study is needed to identify best practice for the introduction and application of survivorship care plans.
Management of work through the seasons of cancer survivorship
Authors: Duijts Saskia F.A.
Published: November 2017

Purpose of review

Survival from cancer has expanded enormously over the past decades. It is estimated that 40–50% of all cancer survivors are of working age at time of diagnosis and thus potentially part of the labor force. The seasons of survivorship can be used as a steppingstone to describe issues regarding employability survivors are dealing with.

Recent findings

The acute survival stage begins at the point of diagnosis. Disclosure of diagnosis, and flexibility of both employers and (occupational) healthcare professionals are important factors in this stage. Extended survival starts when the survivor has completed the basic course of treatment. Survivors become aware that the old normality at work will be difficult to achieve. Problems like fear of recurrence, cognitive, and physical limitations might intensify during this stage and affect work ability. Permanent survival can be called long-term remission. Prospective studies on work-related outcomes and work-related interventions in this stage are rare.

It is important to improve our understanding of the seasons of survival and to explore concepts, such as employability, against the background of these seasons. This perspective may help both survivors and (occupational) healthcare professionals to develop better strategies for dealing with the difficult life event cancer represents in each specific stage.
Single-cell Map of Diverse Immune Phenotypes Driven by the Tumor Microenvironment
Authors: Azizi Elham , Carr Ambrose J. , Plitas George , Cornish Andrew E. , Konopacki Catherine , Prabhakaran Sandhya , Nainys Juozas , Wu Kenmin , Kiseliovas Vaidotas , Setty Manu , Choi Kristy , Fromme Rachel M. , Dao Phuong , McKenney Peter T. , Wasti Ruby C. , Kadaveru Krishna , Mazutis Linas , Rudensky Alexander Y. , Pe’er Dana
Published: November 2017

Knowledge of immune cell phenotypes in the tumor microenvironment is essential for understanding mechanisms of cancer progression and immunotherapy response. We created an immune map of breast cancer using single-cell RNA-seq data from 45,000 immune cells from eight breast carcinomas, as well as matched normal breast tissue, blood, and lymph node. We developed a preprocessing pipeline, SEQC, and a Bayesian clustering and normalization method, Biscuit, to address computational challenges inherent to single-cell data. Despite significant similarity between normal and tumor tissue-resident immune cells, we observed continuous tumor-specific phenotypic expansions driven by environmental cues. Analysis of paired single-cell RNA and T cell receptor (TCR) sequencing data from 27,000 additional T cells revealed the combinatorial impact of TCR utilization on phenotypic diversity. Our results support a model of continuous activation in T cells and do not comport with the macrophage polarization model in cancer, with important implications for characterizing tumor-infiltrating immune cells.
A non-genetic meiotic repair program inferred from spore survival values in fission yeast wild isolates: a clue for an epigenetic ratchet-like model of ageing?
Authors: Marsellach Xavi
Published: November 2017

1.

What is the nature of the ageing process? What is the spore survival, that one would expect upon analysing a self-cross, in a wild fission yeast strain? Could this two research questions be, somehow, related? In this manuscript, I am describing some interesting observations obtained while studying fission yeast spore survival values upon genetic crosses. Early findings brought my attention into mainly studying self-crosses (intra-strain crosses in which any cell can be involved in by matting with a sibling cell). This study, yield some interesting findings. As a summary: 1) most fission yeast self-crosses do show low spore survival values; 2) clonally related strains show a high phenotypic variability in self-cross spore survival values; 3) differences in self-cross spore survival values can be detected when comparing zygotic and azygotic mattings; 4) self-cross spore survival values are highly affected by environmental factors, mainly producing a reduction in the spore survival values; 5) self-cross spore survival values are “recovered” when cells are subjected to several rounds of meiotic divisions; 6) signs of correlation between spore survival and vegetative cell survival (prior to the entry into meiosis) have been observed in this study. All those observations, among others, are discussed as part of an epigenetic variability that exist in fission yeast populations. A cyclical behaviour, of this epigenetic variability it is proposed, defining an underlying ratchet-like epigenetic mechanisms acting in all cells. In this manuscript, I propose that this mechanism, is, indeed, the main cause of the ageing process.
Ecological change points: The strength of density dependence and the loss of history
Authors: Ponciano José M. , Taper Mark L. , Dennis Brian
Published: November 2017

Change points in the dynamics of animal abundances have extensively been recorded in historical time series records. Little attention has been paid to the theoretical dynamic consequences of such change-points. Here we propose a change-point model of stochastic population dynamics. This investigation embodies a shift of attention from the problem of detecting when a change will occur, to another non-trivial puzzle: using ecological theory to understand and predict the post-breakpoint behavior of the population dynamics. The proposed model and the explicit expressions derived here predict and quantify how density dependence modulates the influence of the pre-breakpoint parameters into the post-breakpoint dynamics. Time series transitioning from one stationary distribution to another contain information about where the process was before the change-point, where is it heading and how long it will take to transition, and here this information is explicitly stated. Importantly, our results provide a direct connection of the strength of density dependence with theoretical properties of dynamic systems, such as the concept of resilience. Finally, we illustrate how to harness such information through maximum likelihood estimation for state-space models, and test the model robustness to widely different forms of compensatory dynamics. The model can be used to estimate important quantities in the theory and practice of population recovery.
Re-arrangements in the cytoplasmic distribution of small RNAs following the maternal-to-zygotic transition inDrosophilaembryos
Authors: Cosacak Mehmet Ilyas , Yiğit Hatice , Akgül Bünyamin
Published: November 2017

Small RNAs are known to regulate gene expression during early development. However, the dynamics of interaction between small RNAs and polysomes during this process is largely unknown. 0-1h and 7-8hDrosophilaembryos were fractionated on sucrose density gradients into four fractions based on A254reading (1) translationally inactive messengerribonucleoprotein (mRNP); (2) 60S; (3) monosome; and (4) polysome. Comparative analysis of deep-sequencing reads from fractionated and un-fractionated 0-1h and 8-h embryos revealed development-specific co-sedimentation pattern of small RNAs with the cellular translation machinery. Although most miRNAs did not have a specific preference for any state of the translational machinery, we detected fraction-specific enrichment of some miRNAs such as miR-1-3p, -184-39, 5-5p and 263-5p. More interestingly, we observed dysregulation of a subset of miRNAs in fractionated embryos despite no measurable difference in their amount in unfractionated embryos. Transposon-derived endosiRNAs are over-expressed in 7-8h embryos and are associated mainly with the mRNP fraction. However, transposon-derived piRNAs, which are more abundant in 0-1h embryos, co-sediment primarily with the polysome fractions. These results suggest that there appears to be a complex interplay among the small RNAs with respect to their polysome-cosedimention pattern during early development inDrosophila.
DDX3 is exploited by Arenaviruses to suppress type I interferons and favor their replication
Authors: Loureiro María Eugenia , Zorzetto-Fernandes Andre Luiz , Radoshitzky Sheli , Chi Xiaoli , Dallari Simone , Marooki Nuha , Lèger Psylvia , Foscaldi Sabrina , Sharma Sonia , López Nora , de la Torre Juan Carlos , Bavari Sina , Zúñiga Elina
Published: November 2017

Several arenaviruses cause hemorrhagic fever (HF) diseases that are associated with high morbidity and mortality in humans. Accordingly, HF arenaviruses have been listed as top-priority emerging diseases for which countermeasures are urgently needed. Because arenavirus nucleoprotein (NP) plays critical roles in both virus multiplication and immune-evasion, we used an unbiased proteomic approach to identify NP-interacting proteins in human cells. DDX3, a DEAD-box ATP-dependent-RNA-helicase, interacted with NP in both NP-transfected and virus-infected cells. Importantly, DDX3 deficiency compromised the propagation of both Old and New World arenaviruses, including the HF arenaviruses Lassa and Junin viruses. The DDX3 role in promoting arenavirus multiplication correlated with both a previously un-recognized DDX3 contribution to type I interferon suppression in arenavirus infected cells and a positive effect of DDX3 on viral RNA synthesis. Our results uncover novel mechanisms used by arenavirus to exploit the host machinery and subvert immunity, singling out DDX3 as a potential host target for developing new therapies against highly pathogenic arenaviruses.

AUTHOR SUMMARY

Arenaviruses include severe clinical pathogens causing hemorrhagic fevers and have been recently incorporated by the World Health Organization in a list of critical emerging diseases for which additional research and identification of clinical targets is urgently required. A better understanding of how viral proteins interact with host cellular factors to favor arenavirus multiplication can illuminate novel pipelines on therapeutic strategies. Here we demonstrated that the ATP-dependent RNA helicase DDX3 interacted with the arenavirus nucleoprotein, which displays fundamental functions in different steps of the viral-cycle. Our work also revealed an unexpected new biology on the role that DDX3 might play during viral infections. In sharp contrast to previous studies showing DDX3 enhancement of IFN-I induction, we demonstrated that DDX3 suppressed IFN-I production at late time points after arenavirus infection, contributing to a DDX3 pro-viral effect. We also showed that early after infection, DDX3 pro-viral role was IFN-I independent and was mediated by DDX3 facilitation of viral RNA synthesis without affecting RNA translation. Altogether, our study established DDX3 as a critical host interacting partner of the arenavirus nucleoprotein and demonstrated two previously unrecognized DDX3-dependent strategies by which these deadly viruses exploit the host cellular machinery and suppress immunity.
Combining accurate tumour genome simulation with crowd-sourcing to benchmark somatic structural variant detection
Authors: Lee Anna Y. , Ewing Adam D. , Ellrott Kyle , Hu Yin , Houlahan Kathleen E. , Bare J.Christopher , G. Espiritu Shadrielle Melijah , Huang Vincent , Dang Kristen , Chong Zechen , Caloian Cristian , Yamaguchi Takafumi N. ,   ICGC-TCGA DREAM Somatic Mutation Calling Challenge Participants, Kellen Michael R. , Chen Ken , Norman Thea C. , Friend Stephen H. , Guinney Justin , Stolovitzky Gustavo , Haussler David , Margolin Adam A. , Stuart Joshua M. , Boutros Paul C.
Published: November 2017

Background

The phenotypes of cancer cells are driven in part by somatic structural variants. Structural variants can initiate tumors, enhance their aggressiveness and provide unique therapeutic opportunities. Whole-genome sequencing of tumors can allow exhaustive identification of the specific structural variants present in an individual cancer, facilitating both clinical diagnostics and the discovery of novel mutagenic mechanisms. A plethora of somatic structural variant detection algorithms have been created to enable these discoveries, however there are no systematic benchmarks of them. Rigorous performance evaluation of somatic structural variant detection methods has been challenged by the lack of gold-standards, extensive resource requirements and difficulties arising from the need to share personal genomic information.

Results

To facilitate structural variant detection algorithm evaluations, we create a robust simulation framework for somatic structural variants by extending the BAMSurgeon algorithm. We then organize and enable a crowd-sourced benchmarking within the ICGC-TCGA DREAM Somatic Mutation Calling Challenge (SMC-DNA). We report here the results of structural variant benchmarking on three different tumors, comprising 204 submissions from 15 teams. In addition to ranking methods, we identify characteristic error-profiles of individual algorithms and general trends across them. Surprisingly, we find that ensembles of analysis pipelines do not always outperform the best individual method, indicating a need for new ways to aggregate somatic structural variant detection approaches.

Conclusions

The synthetic tumors and somatic structural variant detection leaderboards remain available as a community benchmarking resource, and BAMSurgeon is available athttps://github.com/adamewing/bamsurgeon.
Dose response relationships for gamma radiation induced chromosomal instability
Authors: Eidelman Y.A. , Slanina S.V. , Pyatenko V.S. , Khvostunov I.K. , Andreev S.G.
Published: November 2017

Different cell lines demonstrate various dose response for radiation-induced chromosomal instability (RICI). To clarify the origin of differences we analyzed own and published data on RICI for four cell lines, V79, TK6, WTK1 and CHO-K1 on the basis of the mechanistic RICI model. We conclude that observable dose-response shapes, both plateau-like and strong dose dependent behavior, may be jointly explained by the same model of RICI. Mechanistic modeling reveals that a variation of certain set of RICI parameters leads to strong modification of dose-response curve.
Antigen-induced but not innate memory CD8 T cells express NKG2D and are recruited to the lung parenchyma upon viral infection
Authors: Grau Morgan , Valsesia Séverine , Mafille Julien , Djebali Sophia , Tomkowiak Martine , Mathieu Anne-Laure , Laubreton Daphné , de Bernard Simon , Jouve Pierre-Emmanuel , Buffat Laurent , Walzer Thierry , Leverrier Yann , Marvel Jacqueline
Published: November 2017

The pool of memory-phenotype CD8 T cells is composed of antigen-induced (AI) and cytokine-induced innate (IN) cells. IN have been described as having similar properties to AI memory cells. However, we found that pathogen-induced AI memory cells can be distinguished from naturally-generated IN memory cells by surface expression of NKG2D. Using this marker, we described the increased functionalities of AI and IN memory CD8 T cells compared to naive cells, as shown by comprehensive analysis of cytokine secretion and gene expression. However, AI differed from IN memory CD8 T cells by their capacity to migrate to the lung parenchyma upon inflammation or infection, a process dependent on their expression of ITGA1/CD49a and ITGA4/CD49d integrins.
A global comparison of the nutritive values of forage plants grown in contrasting environments
Authors: Lee Mark A.
Published: November 2017

Forage plants are valuable because they maintain wild and domesticated herbivores, and sustain the delivery of meat, milk and other commodities. Forage plants contain different quantities of fibre, lignin, minerals and protein, and vary in the proportion of their tissue that can be digested by herbivores. These nutritive components are important determinants of consumer growth rates, reproductive success and behaviour. A dataset was compiled to quantify variation in forage plant nutritive values within- and between-plant species, and to assess variation between plant functional groups and bioclimatic zones. 1,255 geo-located records containing 3,774 measurements of nutritive values for 136 forage plant species grown in 30 countries were obtained from published articles. Spatial variability in forage nutritive values indicated that climate modified plant nutritive values. Forage plants grown in arid and equatorial regions generally contained less digestible material than those grown in temperate and tundra regions; containing more fibre and lignin, and less protein. These patterns may reveal why herbivore body sizes, digestion and migration strategies are different in warmer and drier regions. This dataset also revealed the capacity for variation in the nutrition provided by forage plants. The proportion of the plant tissue that was digestible ranged between species from 2-91%. The amount of fibre contained within plant material ranged by 23-90%, protein by 2-36%, lignin by 1-21% and minerals by 2-22%. Water contents also varied substantially; ranging from 3-89% of standing biomass. On average, grasses and tree foliage contained the most fibre, whilst herbaceous legumes contained the most protein and tree foliage contained the most lignin. However, there were individual species within each functional group that were highly nutritious. This dataset may be used to identify forage plant species with useful traits which can be cultivated to enhance livestock productivity and inform wild herbivore conservation strategies.
Binding of the integrated stress response inhibitor, ISRIB, reveals a regulatory site in the nucleotide exchange factor, elF2B
Authors: Zyryanova Alisa F. , Weis Félix , Faille Alexandre , Abo Alard Akeel , Crespillo-Casado Ana , Harding Heather P. , Allen Felicity , Parts Leopold , Fromont Christophe , Fischer Peter M. , Warren Alan J. , Ron David
Published: November 2017

The Integrated Stress Response (ISR) is a conserved eukaryotic translational and transcriptional program implicated in mammalian metabolism, memory and immunity. The ISR is mediated by stress-induced phosphorylation of translation initiation factor 2 (eIF2) that attenuates the guanine nucleotide exchange factor eIF2B. A chemical inhibitor of the ISR, ISRIB, a bis-O-arylglycolamide, reverses the attenuation of eIF2B by phosphorylated eIF2, protecting mice from neurodegeneration and traumatic brain injury. We report on a cryo-electron microscopy-based structure of ISRIB-bound human eIF2B revealing an ISRIB-binding pocket at the interface between the β and δ regulatory subunits. CRISPR/Cas9 mutagenesis of residues lining this pocket altered the hierarchical cellular response to ISRIB congenersin vivoand ISRIB-bindingin vitro, thus providing chemogenetic support for the functional relevance of ISRIB binding at a distance from known eIF2-eIF2B interaction sites. Our findings point to a hitherto unexpected allosteric site in the eIF2B decamer exploited by ISRIB to regulate translation.
Clusterdv, a simple density-based clustering method that is robust, general and automatic
Authors: Marques João C. , Orger Michael B.
Published: November 2017

How to partition a data set into a set of distinct clusters is a ubiquitous and challenging problem. The fact that data varies widely in features such as cluster shape, cluster number, density distribution, background noise, outliers and degree of overlap, makes it difficult to find a single algorithm that can be broadly applied. One recent method, clusterdp, based on search of density peaks, can be applied successfully to cluster many kinds of data, but it is not fully automatic, and fails on some simple data distributions. We propose an alternative approach, clusterdv, which estimates density dips between points, and allows robust determination of cluster number and distribution across a wide range of data, without any manual parameter adjustment. We show that this method is able to solve a range of synthetic and experimental data sets, where the underlying structure is known, and identifies consistent and meaningful clusters in new behavioral data.

Author summar

It is common that natural phenomena produce groupings, or clusters, in data, that can reveal the underlying processes. However, the form of these clusters can vary arbitrarily, making it challenging to find a single algorithm that identifies their structure correctly, without prior knowledge of the number of groupings or their distribution. We describe a simple clustering algorithm that is fully automatic and is able to correctly identify the number and shape of groupings in data of many types. We expect this algorithm to be useful in finding unknown natural phenomena present in data from a wide range of scientific fields.
Scale-specific analysis of fMRI data on the irregular cortical surface
Authors: Chen Yi , Cichy Radoslaw Martin , Stannat Wilhelm , Haynes John-Dylan
Published: November 2017

To fully characterize the activity patterns on the cerebral cortex as measured with fMRI, the spatial scale of the patterns must be ascertained. Here we address this problem by constructing steerable bandpass filters on the discrete, irregular cortical mesh, using an improved Gaussian smoothing in combination with differential operators of directional derivatives. We demonstrate the utility of the algorithm in two ways. First, using modelling we show that our algorithm yields superior results in numerical precision and spatial uniformity of filter kernels compared to the most widely adopted approach for cortical smoothing. An important interim insight hereby was that the effective scales of information differ from the nominal filter sizes applied to extract them, and thus need to be calculated separately to compare different algorithms on par. Second, we applied the algorithm to an fMRI dataset to assess the scale and pattern form of cortical encoding of information about visual objects in the ventral visual pathway. We found that filtering by our method improved the detection of discriminant information about experimental conditions over previous methods, that the level of categorization (subordinate versus superordinate) of objects was differentially related to the spatial scale of fMRI patterns, and that the spatial scale at which information was encoded increased along the ventral visual pathway. In sum, our results indicate that the proposed algorithm is particularly suited to assess and detect scale-specific information encoding in cortex, and promises further insight into the topography of cortical encoding in the human brain.
A suite of transgenic driver and reporter mouse lines with enhanced brain cell type targeting and functionality
Authors: Daigle Tanya L. , Madisen Linda , Hage Travis A. , Valley Matthew T. , Knoblich Ulf , Larsen Rylan S. , Takeno Marc M. , Huang Lawrence , Gu Hong , Larsen Rachael , Mills Maya , Bosma-Moody Alice , Siverts La’Akea , Walker Miranda , Graybuck Lucas T. , Yao Zizhen , Fong Olivia , Garren Emma , Lenz Garreck , Chavarha Mariya , Pendergraft Julie , Harrington James , Hirokawa Karla E. , Harris Julie A. , McGraw Medea , Ollerenshaw Douglas R. , Smith Kimberly , Baker Christopher A. , Ting Jonathan T. , Sunkin Susan M. , Lecoq Jerome , Lin Michael Z. , Boyden Edward S. , Murphy Gabe J. , da Costa Nuno , Waters Jack , Li Lu , Tasic Bosiljka , Zeng Hongkui
Published: November 2017

Modern genetic approaches are powerful in providing access to diverse types of neurons within the mammalian brain and greatly facilitating the study of their function. We here report a large set of driver and reporter transgenic mouse lines, including 23 new driver lines targeting a variety of cortical and subcortical cell populations and 26 new reporter lines expressing an array of molecular tools. In particular, we describe the TIGRE2.0 transgenic platform and introduce Cre-dependent reporter lines that enable optical physiology, optogenetics, and sparse labeling of genetically-defined cell populations. TIGRE2.0 reporters broke the barrier in transgene expression level of single-copy targeted-insertion transgenesis in a wide range of neuronal types, along with additional advantage of a simplified breeding strategy compared to our first-generation TIGRE lines. These novel transgenic lines greatly expand the repertoire of high-precision genetic tools available to effectively identify, monitor, and manipulate distinct cell types in the mouse brain.
Deciphering eukaryotic cis-regulatory logic with 100 million random promoters
Authors: de Boer Carl G. , Vaishnav Eeshit Dhaval , Sadeh Ronen , Abeyta Esteban Luis , Friedman Nir , Regev Aviv
Published: November 2017

Deciphering cis-regulation, the code by which transcription factors (TFs) interpret regulatory DNA sequence to control gene expression levels, is a long-standing challenge. Previous studies of native or engineered sequences have remained limited in scale. Here, we use random sequences as an alternative, allowing us to measure the expression output of over 100 million synthetic yeast promoters. Random sequences yield a broad range of reproducible expression levels, indicating that the fortuitous binding sites in random DNA are functional. From these data we learn models of transcriptional regulation that predict over 94% of the expression driven from independent test data and nearly 89% from sequences from yeast promoters. These models allow us to characterize the activity of TFs and their interactions with chromatin, and help refine cis-regulatory motifs. We find that strand, position, and helical face preferences of TFs are widespread and depend on interactions with neighboring chromatin. Such massive-throughput regulatory assays of random DNA provide the diverse examples necessary to learn complex models of cis-regulatory logic.
Improving bioinformatics prediction of microRNA targets by ranks aggregation
Authors: Quillet Aurélien , Saad Chadi , Ferry Gaētan , Anouar Youssef , Vergne Nicolas , Lecroq Thierry , Dubessy Christophe
Published: November 2017

microRNAs are non-coding RNAs which down-regulate a large number of target mRNAs and modulate cell activity. Despite continued progress, bioinformatics prediction of microRNA targets remains a challenge since available softwares still suffer from a lack of accuracy and sensitivity. Moreover, these tools show fairly inconsistent results from one another. Thus, in an attempt to circumvent these difficulties, we aggregated all human results of three important prediction algorithms (miRanda, PITA and SVmicrO) showing additional characteristics in order to rerank them into a single list. This database is freely available through a webtool called miRabel (http://bioinfo.univ-rouen.fr/mirabel/) which can take either a list of miRNAs, genes or signaling pathways as search inputs. Receiver Operating Characteristic curves and Precision-Recall curves analysis carried out using experimentally validated data and very large datasets show that miRabel significantly improves the prediction of miRNA targets compared to the three algorithms used separatly. Moreover, using the same analytical methods, miRabel shows significantly better predictions than other popular algorithms such as MBSTAR and miRWalk. Interestingly, a F-score analysis revealed that miRabel also significantly improves the relevance of the top results. The aggregation of results from different databases is therefore a powerful and generalizable approach to many other species to improve miRNA target predictions. Thus, miRabel is an efficient tool to accurately identify miRNA targets and integrate them into a biological context.
Brain Modularity Mediates the Relation between Task Complexity and Performance
Authors: Yue Qiuhai , Martin Randi , Fischer-Baum Simon , Ramos-Nuñez Aurora I. , Ye Fengdan , Deem Michael W.
Published: November 2017

Recent work in cognitive neuroscience has focused on analyzing the brain as a network, rather than as a collection of independent regions. Prior studies taking this approach have found that individual differences in the degree of modularity of the brain network relate to performance on cognitive tasks. However, inconsistent results concerning the direction of this relationship have been obtained, with some tasks showing better performance as modularity increases and other tasks showing worse performance. A recent theoretical model (Chen & Deem, 2015) suggests that these inconsistencies may be explained on the grounds that high-modularity networks favor performance on simple tasks whereas low-modularity networks favor performance on more complex tasks. The current study tests these predictions by relating modularity from resting-state fMRI to performance on a set of simple and complex behavioral tasks. Complex and simple tasks were defined on the basis of whether they did or did not draw on executive attention. Consistent with predictions, we found a negative correlation between individuals’ modularity and their performance on a composite measure combining scores from the complex tasks but a positive correlation with performance on a composite measure combining scores from the simple tasks. These results and theory presented here provide a framework for linking measures of whole brain organization from network neuroscience to cognitive processing.
Modularity of the metabolic gene network as a prognostic biomarker for hepatocellular carcinoma
Authors: Ye Fengdan , Jia Dongya , Lu Mingyang , Levine Herbert , Deem Michael W
Published: November 2017

Abnormal metabolism is an emerging hallmark of cancer. Cancer cells utilize both aerobic glycolysis and oxidative phosphorylation (OXPHOS) for energy production and biomass synthesis. Understanding the metabolic reprogramming in cancer can help design therapies to target metabolism and thereby to improve prognosis. We have previously argued that more malignant tumors are usually characterized by a more modular expression pattern of cancer-associated genes. In this work, we analyzed the expression patterns of metabolism genes in terms of modularity for 371 hepatocellular carcinoma (HCC) samples from the Cancer Genome Atlas (TCGA). We found that higher modularity significantly correlated with glycolytic phenotype, later tumor stages, higher metastatic potential, and cancer recurrence, all of which contributed to poorer prognosis. Among patients with recurred tumor, we found the correlation of higher modularity with worse prognosis during early to mid-progression. Furthermore, we developed metrics to calculate individual modularity, which was shown to be predictive of cancer recurrence and patients’ survival and therefore may serve as a prognostic biomarker. Our overall conclusion is that more aggressive HCC tumors, as judged by decreased host survival probability, had more modular expression patterns of metabolic genes. These results may be used to identify cancer driver genes and for drug design.
Nonequilibrium entropic bounds for Darwinian replicators
Authors: Piñero Jordi , Solé Ricard
Published: November 2017

Life evolved on our planet by means of a combination of Darwinian selection and innovations leading to higher levels of complexity. The emergence and selection of replicating entities is a central problem in prebiotic evolution. Theoretical models have shown how populations of different types of replicating entities exclude or coexist with other classes of replicators. Models are typically kinetic, based on standard replicator equations. On the other hand, the presence of thermodynamical constrains for these systems remain an open question. This is largely due to the lack of a general theory of out of statistical methods for systems far from equilibrium. Nonetheless, a first approach to this problem has been put forward in a series of novel developements in non-equilibrium physics, under the rubric of the extended second law of thermodynamics. The work presented here is twofold: firstly, we review this theoretical framework and provide a brief description of the three fundamental replicator types in prebiotic evolution: parabolic, malthusian and hyperbolic. Finally, we employ these previously mentioned techinques to explore how replicators are constrained by thermodynamics.
Interaction of lecithin-cholesterol acyltransferase with lipid surfaces and apolipoprotein A-I derived peptides: implications for the cofactor mechanism of apolipoprotein A-I
Authors: Casteleijn Marco G. , Parkkila Petteri , Viitala Tapani , Koivuniemi Artturi
Published: November 2017

Lecithin-cholesterol acyltransferase (LCAT) is an enzyme responsible for the formation of cholesteryl esters from cholesterol (CHOL) and phospholipid (PL) molecules in high-density lipoprotein (HDL) particles that play a crucial role in the reverse cholesterol transport and the development of coronary heart disease (CHD). However, it is poorly understood how LCAT interacts with lipoprotein surfaces and how apolipoprotein A-I (apoA-I) activates it. Thus, here we have studied the interactions between LCAT and lipids through extensive atomistic and coarse-grained molecular dynamics simulations to reveal mechanistic details behind the cholesterol esterification process catalyzed by LCAT. In addition, we studied the binding of LCAT to apoA-I derived peptides, and their effect on LCAT lipid association utilizing experimental surface sensitive biophysical methods. Our simulations show that LCAT anchors itself to lipoprotein surfaces by utilizing non-polar amino acids located in the membrane-binding domain and the active site tunnel opening. Meanwhile, the membrane anchoring hydrophobic amino acids attract cholesterol molecules next to them. The results also highlight the role of the lid-loop in the lipid binding and conformation of LCAT with respect to the lipid surface. The apoA-I derived peptides from the LCAT activating region bind to LCAT and promote its lipid surface interactions, although some of these peptides do not bind lipids individually. By means of free-energy calculations we provided a hypothetical explanation for this mechanism. We also found that the transfer free-energy of PL to the active site is consistent with the activation energy of LCAT. Furthermore, the entry of CHOL molecules into the active site becomes highly favorable by the acylation of SER181. The results provide substantial mechanistic insights concerning the activity of LCAT that may lead to the development of novel pharmacological agents preventing CHD in the future.
Control of bacterial population density with population feedback and molecular sequestration
Authors: McCardell Reed D. , Huang Shan , Green Leopold N. , Murray Richard M.
Published: November 2017

Genetic engineering technology has become sophisticated enough to allow precise manipulation of bacterial genetic material. Engineering efforts with these technologies have created modified bacteria for various medical, industrial, and environmental purposes, but organisms designed for specific functions require improvements in stability, longevity, or efficiency of function. Most bacteria live in multispecies communities, whose composition may be closely linked to the effect the community has on the environment. Bacterial engineering efforts will benefit from building communities with regulated compositions, which will enable more stable and powerful community functions.

We present a design of a synthetic two member bacterial community capable of maintaining its composition at a defined ratio of [cell type 1]: [cell type 2]. We have constructed the genetic motif that will act in each cell in the two member community, containing an AHL-based negative feedback loop that activates ccdB toxin, which caps population density with increasing feedback strength. It also contains one of two ccdB sequestration modules, either the ccdA protein antitoxin, or an RNA device which prevents transcription and translation of ccdB mRNA, that rescues capped population density with induction. We compare absorbance and colony counting methods of estimating bacterial population density, finding that absorbance-based methods overestimate viable population density when ccdB toxin is used to control population density.

Prior modeling results show that two cell types containing this genetic circuit motif that reciprocally activate the other’s ccdB sequestration device will establish a steady state ratio of cell types. Experimental testing and tuning the full two member community will help us improve our modeling of multi-member bacterial communities, learn more about the strengths and weaknesses of our design for community composition control, and identify general principles of design of compositionally-regulated microbial communities.
AtRsgAfromArabidopsis thalianacontrols maturation of the small subunit of the chloroplast ribosome
Authors: Janowski Marcin , Zoschke Reimo , Scharff Lars , Jaime Silvia Martinez , Ferrari Camilla , Proost Sebastian , Omranian Nooshin , Musialak-Lange Magdalena , Nikoloski Zoran , Graf Alexander , Schöttler Mark A. , Sampathkumar Arun , Vaid Neha , Mutwil Marek
Published: November 2017

Plastid ribosomes are very similar in structure and function to ribosomes of their bacterial ancestors. Since ribosome biogenesis is not thermodynamically favourable at biological conditions, it requires activity of many assembly factors. Here, we have characterized a homolog of bacterialrsgAinArabidopsis thalianaand show that it can complement the bacterial homolog. Functional characterization of a strong mutant in Arabidopsis revealed that the protein is essential for plant viability, while a weak mutant produced dwarf, chlorotic plants that incorporated immature pre-16S ribosomal RNA into translating ribosomes. Physiological analysis of the mutant plants revealed smaller, but more numerous chloroplasts in the mesophyll cells, reduction of chlorophyllaandb, depletion of proplastids from the rib meristem and decreased photosynthetic electron transport rate and efficiency. Comparative RNA-sequencing and proteomic analysis of the weak mutant and wild-type plants revealed that various biotic stress-related, transcriptional regulation and post-transcriptional modification pathways were repressed in the mutant. Intriguingly, while nuclear- and chloroplast-encoded photosynthesis-related proteins were less abundant in the mutant, the corresponding transcripts were upregulated, suggesting an elaborate compensatory mechanism, potentially via differentially active retrograde signalling pathways. To conclude, this study reveals a new chloroplast ribosome assembly factor and outlines the transcriptomic and proteomic responses of the compensatory mechanism activated during decreased chloroplast function.

Significance statement

AtRsgA is an assembly factor necessary for maturation of the small subunit of the chloroplast ribosome. Depletion of AtRsgA leads to dwarfed, chlorotic plants and smaller, but more numerous chloroplasts. Large-scale transcriptomic and proteomic analysis revealed that chloroplast-encoded and - targeted proteins were less abundant, while the corresponding transcripts were upregulated in the mutant. We analyse the transcriptional responses of several retrograde signalling pathways to suggest a mechanism underlying this compensatory response.
Cell-free prototyping strategies for enhancing the sustainable production of polyhydroxyalkanoates bioplastics
Authors: Kelwick Richard , Ricci Luca , Chee Soo Mei , Bell David , Webb Alexander J. , Freemont Paul S.
Published: November 2017

The polyhydroxyalkanoates are a group of microbially-produced biopolymers that have been proposed as sustainable alternatives to several oil-derived plastics. However, polyhydroxyalkanoates are currently more expensive to produce than oil-derived plastics and therefore, more efficient production processes would be desirable. Cell-free transcription-translation-based metabolic engineering strategies have been previously used to optimise several different biosynthetic pathways but not the polyhydroxyalkanoates biosynthetic pathways. Here we have developed several Escherichia coli cell-free transcription-translation-based systems for in vitro prototyping of polyhydroxyalkanoates biosynthetic operons, and also for screening relevant metabolite recycling enzymes. These cell-free transcription-translation reactions were customised through the addition of whey permeate, an industrial waste that has been previously used as a low-cost feedstock for optimising in vivo polyhydroxyalkanoates production. We found that the inclusion of an optimal concentration of whey permeate enhanced relative cell-free GFPmut3b production by ~20% compared to control reactions that did not include whey permeate. An analysis of pH in our cell-free reactions suggests that the observed increase in GFPmut3b production was likely through enhanced ATP generation, as a consequence of the glycolytic processing of lactose present in whey permeate. We also found that whey permeate enhanced cell-free reactions produced ~3μM (R)-3HB-CoA, whilst, coupled cell-free biotransformation/transcription-translation reactions produced a ten-fold greater yield of (R)-3HB-CoA. These reactions were also used to characterise a Clostridium propionicum propionyl CoA transferase enzyme that can recycle Acetyl-CoA. Together our data demonstrate that cell-free approaches can be used to complement in vivo workflows for identifying additional strategies for optimising polyhydroxyalkanoates production.
Decrease of Nibrin expression in chronic hypoxia is associated with hypoxia-induced chemoresistance in medulloblastoma cells
Authors: Cowman Sophie , Fan Yuen Ngan , Pizer Barry , Sée Violaine
Published: December 2017

Solid tumours are less oxygenated than normal tissues. This is called tumour hypoxia and leads to resistance to radiotherapy and chemotherapy. The molecular mechanisms underlying such resistance have been investigated in a range of tumour types, including the adult brain tumours glioblastoma, yet little is known for paediatric brain tumours. Medulloblastoma (MB) is the most common malignant brain tumour in children. Here we used a common MB cell line (D283-MED), to investigate the mechanisms of chemo and radio-resistance in MB, comparing to another MB cell line (MEB-Med8A) and to a widely used glioblastoma cell line (U87MG). In D283-MED and U87MG, chronic hypoxia (5 days), but not acute hypoxia (24 h) induced resistance to etoposide and X-ray irradiation. This acquired resistance upon chronic hypoxia was much less pronounced in MEB-Med8A cells. Using a transcriptomic approach in D283-MED cells, we found a large transcriptional remodelling upon long term hypoxia, in particular the expression of a number of genes involved in detection and repair of double strand breaks (DSB) was altered. The levels of Nibrin (NBN) and MRE11, members of the MRN complex (MRE11/Rad50/NBN) responsible for DSB recognition, were significantly down-regulated. This was associated with a reduction of Ataxia Telangiectasia Mutated (ATM) activation by etoposide, indicating a profound dampening of the DNA damage signalling in hypoxic conditions. As a consequence, p53 activation by etoposide was reduced, and cell survival enhanced. Whilst U87MG shared the same dampened p53 activity, upon chemotherapeutic drug treatment in chronic hypoxic conditions, these cells used a different mechanism, independent of the DNA damage pathway. Together our results demonstrate a new mechanism explaining hypoxia-induced resistance involving the alteration of the response to DSB, but also highlight the cell type to cell type diversity and the necessity to take into account the differing tumour genetic make-up when considering re-sensitisation therapeutic protocols.