bluuebunny/crossref_metadata_2025 huggingface dataset:
New Constituents from Gymnocarpos decander
Authors: Bechlem Houria , Mencherini Teresa , Bouheroum Mohamed , Benayache Samir , Cotugno Roberta , Braca Alessandra , De Tommasi Nunziatina
Published: May 2017

The phytochemical investigation of Gymnocarpos decander aerial parts extract afforded two new saponins, 3-O-β-D-glucuronopyranosyl-2β,3β,16α,23-tetrahydroxyolean-12-en-28-O-β-D-apiofuranosyl-(1 → 3)-β-D-xylopyranosyl-(1 → 4)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosyl ester (1), 3-O-β-D-glucuronopyranosyl-2β,3β,16α-trihydroxyolean-12-en-28-O-α-L-rhamnopyranosyl-(1 → 3)-β-D-xylopyranosyl-(1 → 4)-α-L-rhamnopyranosyl-(1 → 2)-α-L-arabinopyranosyl ester (2), and three new flavonol glycosides, isorhamnetin 3-O-2′′′′-O-acetyl−β-D-xylopyranosyl-(1 → 6)-[β-D-apiofuranosyl-(1 → 2)]-β-D-glucopyranoside (3), isorhamnetin 3-O-2‴-O-acetyl−β-D-xylopyranosyl-(1 → 6)-β-D-glucopyranoside (4), and quercetin 3-O-2‴-O-acetyl−β-D-xylopyranosyl-(1 → 6)-β-D-glucopyranoside (5), together with three known compounds. Their structures were determined by spectroscopic methods including 1D and 2D NMR analysis and high-resolution mass spectrometry. The new isolates were investigated for their potential cytotoxic activity on three cancer cell lines. Compounds 1 and 2 showed moderate antiproliferative activity.
Modelling the susceptibility of pine stands to bark stripping by Chacma baboons (Papio ursinus) in the Mpumalanga Province of South Africa
Authors: Germishuizen Ilaria , Peerbhay Kabir , Ismail Riyad
Published: May 2017

Context Commercial pine (Pinus spp.) plantations in southern Africa have been subjected to bark stripping by Chacma baboons (Papio ursinus) for many decades, resulting in severe financial losses to producers. The drivers of this behaviour are not fully understood and have been partially attributed to resource distribution and availability. Aims The study sought to develop a spatially explicit ecological-risk model for bark stripping by baboons to understand the environmental factors associated with the presence of damage in the pine plantations of the Mpumalanga province of South Africa. Methods The model was developed in Random Forests, a machine learning algorithm. Baboon damage information was collected through systematic surveys of forest plantations conducted annually. Environmental predictors included aspects of climate, topography and compartment-specific attributes. The model was applied to the pine plantations of the study area for risk evaluation. Key results The Random Forests classifier was successful in predicting damage occurrence (F1 score=0.84, area under curve (AUC)=0.96). Variable predictors that contributed most to the model classification accuracy were related to pine-stand characteristics, with the age of trees being the most important predictor, followed by species, site index and altitude. Variables pertaining to the environment surrounding a pine stand did not contribute substantially to the model performance. Key conclusions (1) The study suggests that bark stripping is influenced by compartment attributes; (2) predicted risk of bark stripping is higher in stands above the age of 5 years planted on high-productivity forestry sites, where site index (SI) is above 25; (3) presence of damage is not related to the proximity to natural areas; (4) further studies are required to investigate ecological and behavioural patterns associated with bark stripping. Implications The model provides a tool for understanding the potential extent of the risk of bark stripping by baboons within this region and it can be applied to other forestry areas in South Africa for risk evaluation. It contributes towards the assessment of natural hazards potentially affecting pine plantations and supports the development of risk-management strategies by forest managers. The model highlights opportunities for cultural interventions that may be tested for damage control.
The Court of Justice of the European Union
Authors: Arnull Anthony
Published: May 2017

‘The Court of Justice of the European Union’ explains that the basic duty of the CJEU is to ensure that ‘the law is observed’ in the interpretation and application of the EU Treaties. Most cases brought before the CJEU are either direct actions that start and finish in Luxembourg, or references for preliminary rulings which originate in a national court that needs guidance on the effect of EU law before giving judgment. The most important parts of the CJEU are the Court of Justice and the General Court. These are described, along with the judicial approach of the CJEU.
Enforcing EU law
Authors: Arnull Anthony
Published: May 2017

What are the CJEU’s powers? ‘Enforcing EU law’ considers three of the most important. Infringement proceedings assess claims by the Commission that Member States have failed to do what the Treaties require of them. If such a claim is successful, financial sanctions may be imposed on the State concerned. The action for annulment allows the validity of EU acts to be challenged and enables the CJEU to ensure that the other institutions act within the limits of their powers. The preliminary rulings procedure is the ‘keystone’ of the judicial system established by the Treaties and involves helping national courts to apply EU law correctly.
MD-TASK: a software suite for analyzing molecular dynamics trajectories
Authors: Brown David K , Penkler David L , Sheik Amamuddy Olivier , Ross Caroline , Atilgan Ali Rana , Atilgan Canan , Tastan Bishop Özlem
Published: May 2017

Molecular dynamics (MD) determines the physical motions of atoms of a biological macromolecule in a cell-like environment and is an important method in structural bioinformatics. Traditionally, measurements such as root mean square deviation, root mean square fluctuation, radius of gyration, and various energy measures have been used to analyze MD simulations. Here, we present MD-TASK, a novel software suite that employs graph theory techniques, perturbation response scanning, and dynamic cross-correlation to provide unique ways for analyzing MD trajectories.

Availability and implementation

MD-TASK has been open-sourced and is available for download from https://github.com/RUBi-ZA/MD-TASK, implemented in Python and supported on Linux/Unix.
Automatic fish species classification in underwater videos: exploiting pre-trained deep neural network models to compensate for limited labelled data
Authors: Siddiqui Shoaib Ahmed , Salman Ahmad , Malik Muhammad Imran , Shafait Faisal , Mian Ajmal , Shortis Mark R , Harvey Euan S
Published: May 2017

There is a need for automatic systems that can reliably detect, track and classify fish and other marine species in underwater videos without human intervention. Conventional computer vision techniques do not perform well in underwater conditions where the background is complex and the shape and textural features of fish are subtle. Data-driven classification models like neural networks require a huge amount of labelled data, otherwise they tend to over-fit to the training data and fail on unseen test data which is not involved in training. We present a state-of-the-art computer vision method for fine-grained fish species classification based on deep learning techniques. A cross-layer pooling algorithm using a pre-trained Convolutional Neural Network as a generalized feature detector is proposed, thus avoiding the need for a large amount of training data. Classification on test data is performed by a SVM on the features computed through the proposed method, resulting in classification accuracy of 94.3% for fish species from typical underwater video imagery captured off the coast of Western Australia. This research advocates that the development of automated classification systems which can identify fish from underwater video imagery is feasible and a cost-effective alternative to manual identification by humans.
Mass production and industrial applications of graphene materials
Authors: Zhu Yanwu , Ji Hengxing , Cheng Hui-Ming , Ruoff Rodney S
Published: May 2017

Graphene is considered a promising material for industrial application based on the intensive laboratory-scale research in the fields of physics, chemistry, materials science and engineering, and biology over the last decade. Many companies have thus started to pursue graphene materials on a scale of tons (for the flake material) or hundreds of thousands of square meters (for the film material) for industrial applications. Though the graphene industry is still in its early stages, very significant progress in mass production and certain industrial applications has become obvious. In this report, we aim to give a brief review of the mass production of graphene materials for some industrial applications and summarize some features or challenges for graphene in the marketplace.
The Deposits Channel of Monetary Policy*
Authors: Drechsler Itamar , Savov Alexi , Schnabl Philipp
Published: May 2017

We present a new channel for the transmission of monetary policy, the deposits channel. We show that when the Fed funds rate rises, banks widen the spreads they charge on deposits, and deposits flow out of the banking system. We present a model where this is due to market power in deposit markets. Consistent with the market power mechanism, deposit spreads increase more and deposits flow out more in concentrated markets. This is true even when we control for lending opportunities by only comparing different branches of the same bank. Since deposits are the main source of liquid assets for households, the deposits channel can explain the observed strong relationship between the liquidity premium and the Fed funds rate. Since deposits are also a uniquely stable funding source for banks, the deposits channel impacts bank lending. When the Fed funds rate rises, banks that raise deposits in concentrated markets contract their lending by more than other banks. Our estimates imply that the deposits channel can account for the entire transmission of monetary policy through bank balance sheets.
The Philae lander mission and science overview
Authors: Boehnhardt Hermann , Bibring Jean-Pierre , Apathy Istvan , Auster Hans Ulrich , Ercoli Finzi Amalia , Goesmann Fred , Klingelhöfer Göstar , Knapmeyer Martin , Kofman Wlodek , Krüger Harald , Mottola Stefano , Schmidt Walter , Seidensticker Klaus , Spohn Tilman , Wright Ian
Published: May 2017

The Philae lander accomplished the first soft landing and the first scientific experiments of a human-made spacecraft on the surface of a comet. Planned, expected and unexpected activities and events happened during the descent, the touch-downs, the hopping across and the stay and operations on the surface. The key results were obtained during 12–14 November 2014, at 3 AU from the Sun, during the 63 h long period of the descent and of the first science sequence on the surface. Thereafter, Philae went into hibernation, waking up again in late April 2015 with subsequent communication periods with Earth (via the orbiter), too short to enable new scientific activities. The science return of the mission comes from eight of the 10 instruments on-board and focuses on morphological, thermal, mechanical and electrical properties of the surface as well as on the surface composition. It allows a first characterization of the local environment of the touch-down and landing sites. Unique conclusions on the organics in the cometary material, the nucleus interior, the comet formation and evolution became available through measurements of the Philae lander in the context of the Rosetta mission.

This article is part of the themed issue ‘Cometary science after Rosetta’.
D2O and HDS in the coma of 67P/Churyumov–Gerasimenko
Authors: Altwegg K. , Balsiger H. , Berthelier J. J. , Bieler A. , Calmonte U. , De Keyser J. , Fiethe B. , Fuselier S. A. , Gasc S. , Gombosi T. I. , Owen T. , Le Roy L. , Rubin M. , Sémon T. , Tzou C.-Y.
Published: May 2017

The European Rosetta mission has been following comet 67P/Churyumov–Gerasimenko for 2 years, studying the nucleus and coma in great detail. For most of these 2 years the Rosetta Orbiter Sensor for Ion and Neutral Analysis (ROSINA) has analysed the volatile part of the coma. With its high mass resolution and sensitivity it was able to not only detect deuterated water HDO, but also doubly deuterated water, D2O and deuterated hydrogen sulfide HDS. The ratios for [HDO]/[H2O], [D2O]/[HDO] and [HDS]/[H2S] derived from our measurements are (1.05 ± 0.14) × 10−3, (1.80 ± 0.9) × 10−2and (1.2 ± 0.3) × 10−3, respectively. These results yield a very high ratio of 17 for [D2O]/[HDO] relative to [HDO]/[H2O]. Statistically one would expect just 1/4. Such a high value can be explained by cometary water coming unprocessed from the presolar cloud, where water is formed on grains, leading to high deuterium fractionation. The high [HDS]/[H2S] ratio is compatible with upper limits determined in low-mass star-forming regions and also points to a direct correlation of cometary H2S with presolar grain surface chemistry.

This article is part of the themed issue ‘Cometary science after Rosetta’.
Comets as a possible source of nanodust in the Solar System cloud and in planetary debris discs
Authors: Mann Ingrid
Published: May 2017

Comets, comet-like objects and their fragments are the most plausible source for the dust in both the inner heliosphere and planetary debris discs around other stars. The smallest size of dust particles in debris discs is not known and recent observational results suggest that the size distribution of the dust extends down to sizes of a few nanometres or a few tens of nanometres. In the Solar System, electric field measurements from spacecraft observe events that are explained with high-velocity impacts of nanometre-sized dust. In some planetary debris discs an observed mid- to near-infrared emission supposedly results from hot dust located in the vicinity of the star. And the observed emission is characteristic of dust of sizes a few tens of nanometres. Rosetta observations, on the other hand, provide little information on the presence of nanodust near comet 67P/Churyumov–Gerasimenko. This article describes why this is not in contradiction to the observations of nanodust in the heliosphere and in planetary debris discs. The direct ejection of nanodust from the nucleus of the comet would not contribute significantly to the observed nanodust fluxes. We discuss a scenario that nanodust forms in the interplanetary dust cloud through the high-velocity collision process in the interplanetary medium for which the production rates are highest near the Sun. Likewise, fragmentation by collisions occurs near the star in planetary debris discs. The collisional fragmentation process in the inner Solar System occurs at similar velocities to those of the collisional evolution in the interstellar medium. A question for future studies is whether there is a common magic size of the smallest collision fragments and what determines this size.

This article is part of the themed issue ‘Cometary science after Rosetta’.
Cometary science after Rosetta
Authors: Jones Geraint H. , Knight Matthew M. , Fitzsimmons Alan , Taylor Matt G. G. T.
Published: May 2017

The European Space Agency’s
Rosetta
mission ended operations on 30 September 2016 having spent over 2 years in close proximity to its target comet, 67P/Churyumov–Gerasimenko. Shortly before this, in summer 2016, a discussion meeting was held to examine how the results of the mission could be framed in terms of cometary and solar system science in general. This paper provides a brief history of the
Rosetta
mission, and gives an overview of the meeting and the contents of this associated special issue.

This article is part of the themed issue ‘Cometary science after Rosetta’.
Germlinede novomutation clusters arise during oocyte aging in genomic regions with increased double-strand break incidence
Authors: Goldmann Jakob M. , Seplyarskiy Vladimir B. , Wong Wendy S.W. , Vilboux Thierry , Bodian Dale L. , Solomon Benjamin D. , Veltman Joris A. , Deeken John F. , Gilissen Christian , Niederhuber John E.
Published: May 2017

Clustering of mutations has been found both in somatic mutations from cancer genomes and in germlinede novomutations (DNMs). We identified 1,755 clustered DNMs (cDNMs) within whole-genome sequencing data from 1,291 parent-offspring trios and investigated the underlying mutational mechanisms. We found that the number of clusters on the maternalallele was positively correlated with maternal age and that these consist of more individual mutations with larger intra-mutational distances compared to paternal clusters. More than 50% of maternal clusters were located on chromosomes 8, 9 and 16, in regions with an overall increased maternal mutation rate. Maternal clusters in these regions showed a distinct mutation signature characterized by C>G mutations. Finally, we found that maternal clusters associate with processes involving double-stranded-breaks (DSBs) such as meiotic gene conversions andde novodeletions events. These findings suggest accumulation of DSB-induced mutations throughout oocyte aging as an underlying mechanism leading to maternal mutation clusters.
Large-Scale Evolutionary Patterns of Protein Domain Distributions in Eukaryotes
Authors: Parikesit Arli A. , Stadler Peter F. , Prohaska Sonja J.
Published: May 2017

The genomic inventory of protein domains is an important indicator of an organism’s regulatory and metabolic capabilities. Existing gene annotations, however, can be plagued by substantial ascertainment biases that make it difficult to obtain and compare quantitative domain data. We find that quantitative trends across the Eukarya can be investigated based on a combination of gene prediction and standard domain annotation pipelines. Species-specific training is required, however, to account for the genomic peculiarities in many lineages. In contrast to earlier studies we find wide-spread statistically significant avoidance of protein domains associated with distinct functional high-level gene-ontology terms.

1998 ACM Subject ClassificationJ.3 Life and Medical Sciences
Acquisition of cell migration defines NK cell differentiation from hematopoietic stem cell precursors
Authors: Lee Barclay J. , Mace Emily M.
Published: May 2017

Human natural killer (NK) cells are generated from CD34+precursors and can be differentiatedin vitroby co-culture with developmentally supportive stromal cells. Despite the requirement for stromal cell contact in this process, the nature of these contacts has been poorly defined. We have previously identified a requirement for NK cell signaling receptors associated with terminal maturation in NK cell migration. However, the relationship between NK cell migration and differentiation is still unclear. Here, we perform continuous long-term imaging and tracking of NK cell progenitors undergoingin vitrodifferentiation. We demonstrate that NK cell precursors can be tracked over long time periods on the order of weeks by utilizing phase-contrast microscopy, and show that these cells acquire increasing motility as they mature. Additionally, we observe that NK cells display a more heterogeneous range of migratory behaviors at later stages of development, with the acquisition of complex modes of migration that are associated with terminal maturation. Together these data demonstrate previously unknown migratory behaviors of innate lymphocytes undergoing lineage differentiation revealed by long-term imaging and analysis workflows.
Cooperative interactions enable singular olfactory receptor expression
Authors: Monahan K. , Schieren I. , Cheung J. , Mumbey-Wafula A. , Monuki E.S. , Lomvardas S.
Published: May 2017

The monogenic and monoallelic expression of only one out of > 1000 olfactory receptor (ORs) genes requires the formation of large heterochromatic chromatin domains that sequester the OR gene clusters. Within these domains, intergenic transcriptional enhancers evade heterochromatic silencing and converge into interchromosomal hubs that assemble over the transcriptionally active OR. The significance of this nuclear organization in OR choice remains elusive. Here, we show that transcription factors Lhx2 and Ebf specify OR enhancers by binding in a functionally cooperative fashion to stereotypically spaced motifs that defy heterochromatin. Specific displacement of Lhx2 and Ebf from OR enhancers resulted in pervasive, long-range, andtransdownregulation of OR transcription, whereas pre-assembly of a multi-enhancer hub increased the frequency of OR choice incis. Our data provide genetic support for the requirement and sufficiency of interchromosomal interactions in singular OR choice and generate general regulatory principles for stochastic, mutually exclusive gene expression programs.
Chondroitin Sulfate Elicits Systemic Pathogenesis In Mice By Interfering With Gut Microbiota Homeostasis
Authors: Liao Tao , Chen Yan-Ping , Huang Shui-Qing , Tan Li-Li , Li Chang-Qing , Huang Xin-An , Xu Qin , Wang Qi , Zeng Qing-Ping
Published: May 2017

Whether chondroitin sulfate (CS), a common ingredient naturally occurring in livestock and poultry products, improves osteoarthritis remains debating. Here, we show for the first time that CS induces steatogenesis, atherogenesis, and dementia-like pathogenesis in mice. Gut microbiome analysis revealed the sulfatase-secreting bacteriaRikenellaand the sulfate-reducing bacteriaDesulfovibrioare enriched. Surprisingly, berberine use boosts CS-induced multi-loci inflammatory manifestations by further increasing the abundance ofRikenellaandDesulfovibrio, whereas cephalosporin reinforces the colon mucus barrier via flourishingAkkermansia muciniphilaand upregulating mucin expression. Mechanistically, berberine aggravates mucus lining injury by prompting mucin degradation, endotoxin leakage, neutralizing antibody induction, pro-inflammatory cytokine burst, lactic acid accumulation and energy currency depletion in multiple organs and tissues. Taken together, CS evokes the early-phase pathogenesis toward steatohepatitis, atherosclerosis, and dementia upon augmenting gut opportunistic infection, and a sustained antibiotic monotherapy does not deprive the risk of CS-driven systemic inflammatory disorders.
Phosphate is the third nutrient monitored by TOR inCandida albicansand provides a target for fungal-specific indirect TOR inhibition
Authors: Liu Ning-Ning , Flanagan Peter , Zeng Jumei , Jani Niketa , Cardenas Maria E. , Moran Gary P. , Köhler Julia R.
Published: May 2017

The TOR pathway regulates morphogenesis and responses to host cells in the fungal pathogenCandida albicans. Eukaryotic TOR complex 1 (TORC1) induces growth and proliferation in response to nitrogen and carbon source availability. Our unbiased genetic approach seeking new components of TORC1 signaling inC. albicansrevealed that the phosphate transporter Pho84 is required for normal TORC1 activity. We found that mutants inPHO84are hypersensitive to rapamycin and, in response to phosphate feeding, generate less phosphorylated ribosomal protein S6 (P-S6) than wild type. The small GTPase Gtr1, a component of the TORC1-activating EGO complex, links Pho84 to TORC1. Mutants in Gtr1, but not in another TORC1-activating GTPase, Rhb1, are defective in the P-S6 response to phosphate. Overexpression of Gtr1 and of a constitutively active Gtr1Q67Lmutant suppress TORC1-related defects. InS. cerevisiae pho84mutants, constitutively active Gtr1 suppresses a TORC1 signaling defect but does not rescue rapamycin hypersensitivity. Hence connections from phosphate homeostasis to TORC1 may differ betweenC. albicansandS. cerevisiae. The converse direction of signaling, from TORC1 to the phosphate homeostasis (PHO) regulon, previously observed inS. cerevisiae, was genetically demonstrated inC. albicansusing conditionalTOR1alleles. A small molecule inhibitor of Pho84, an FDA-approved drug, inhibits TORC1 signaling and potentiates the activity of the antifungals amphotericin B and micafungin. Anabolic TORC1-dependent processes require significant amounts of phosphate. Our study demonstrates that phosphate availability is monitored and also controlled by TORC1, and that TORC1 can be indirectly targeted by inhibiting Pho84.

Significance

The human fungal pathogenCandida albicansuses the TOR signaling pathway to contend with varying host environments and thereby regulate cell growth. Seeking novel components of theC. albicansTOR pathway we identified a cell-surface phosphate importer, Pho84, and its molecular link to TOR complex 1 (TORC1). Since phosphorus is a critical element for anabolic processes like DNA replication, ribosome biogenesis, translation and membrane biosynthesis, TORC1 monitors its availability in regulating these processes. By depleting the central kinase in the TORC1 pathway, we showed that TORC1 signaling modulates regulation of phosphate acquisition. An FDA-approved small-molecule inhibitor of Pho84 inhibits TORC1 signaling and potentiates the activity of the gold-standard antifungal amphotericin B and the echinocandin micafungin.
Global effects of focal brain tumours on functional complexity and network robustness
Authors: Hart Michael G , Romero-Garcia Rafael , Price Stephen J , Suckling John
Published: May 2017

Background

Neurosurgical management of brain tumours has entered a new paradigm of supra-marginal resections that demands thorough understanding of their peri-tumoural functional effects. Historically the effects of tumours have been considered as local, and long-range effects have not been considered. This work tests the hypothesis that focal tumours affect the brain at a global level producing long-range gradients in cortical function.

Methods

Resting state functional (f)MRI data were acquired from 11 participants with glioblastoma and split into discovery and validation datasets. Fractal complexity was computed with a wavelet-based estimator of the Hurst exponent. Distance related effects of the tumours were tested with a tumour mask dilation technique and parcellation of the underlying Hurst maps. Functional connectivity networks were constructed and validated with different parcellation and statistical dependency methods prior to graph theory analysis.

Results

Fractal complexity, measured through the Hurst exponent and tumour mask dilation technique, demonstrates a penumbra of suppression in the peri-tumoural region. At a global level, as distance from the tumour increases, this initial suppression is balanced by a subsequent over-activity before finally normalizing. These effects were best fit by a quadratic model, and were consistent across different network construction pipelines. The Hurst exponent was significantly correlated with multiple graph theory measures of centrality including network robustness, but graph theory measures did not demonstrate distance dependent effects.

Conclusions

This work provides evidence to support the theory that focal brain tumours produce long-range and non-linear gradients in function. Consequently the effects of focal lesions, and the resultant clinical effects, need to be interpreted in terms of the global changes on whole brain functional complexity and network architecture rather than purely in terms of functional localisation. Determining whether the peri-tumoural changes represent adaption or potential plasticity, for example, may facilitate extended resection of the tumour without functional cost.
Parsing of compositions and microstructure characteristics for rust-spots of pear pericarp
Authors: Nan Lijun , Chen Shaobo , Li Yashan , Liu Ya , Jiang Ying , Yang Yan , Xu Chengdong , Chen Guogang
Published: May 2017

The commercial value of Kurles pears pericarp, a popular and favored fruit for its unique aroma and refreshingly crisp texture, had sharply decreased because of a rust breakout of the beloved pear in China during the atmosphere-controlled storage. High performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) were used to analyze rust spots on the pericarp of Kurle pears. Therefore, the chemical compounds of four various eluates, originating from the rust-colored substance collected from the pears pericarp effected, were identified successfully for the first time, which were just rhein, aloe-emodin, chrysophanol and emodin, respectively. Taken together with microstructure characteristics for rust-spots of Kurle pear pericarp, it was no doubt that these eluates were the main factors affecting the rust spots on the pericarp of the Kurle pears during the atmosphere-controlled storage, which was a sign and consequence resisting the undesirable stress of the external environment.
Spatial specificity of auxin responses coordinates wood formation
Authors: Brackmann Klaus , Jouannet Virginie , Qi Jiyan , Schlamp Theresa , Grünwald Karin , Sanchez Pablo , Greb Thomas
Published: May 2017

Spatial organization of signaling events of the phytohormone auxin is fundamental for maintaining a dynamic transition from plant stem cells to differentiated descendants. The cambium, the stem cell niche mediating wood formation, fundamentally depends on auxin signaling but its exact role and spatial organization is obscure. Here, we show that, while auxin signaling levels increase in differentiating cambium descendants, a moderate level of signaling in cambial stem cells is essential for cambium activity. We identify the auxin-dependent transcription factor ARF5/MONOPTEROS to cell-autonomously restrict the number of stem cells by attenuating the activity of the stem cell promotingWOX4gene. In contrast, ARF3 and ARF4 function as cambium activators in a redundant fashion from outside of WOX4-expressing cells. Our results reveal an influence of auxin signaling on distinct cambium features by specific signaling components and allow the conceptual integration of plant stem cell systems with distinct anatomies.
Optogenetic single-cell control of transcription achieves mRNA tunability and reduced variability
Authors: Rullan Marc , Benzinger Dirk , Schmidt Gregor W. , Gupta Ankit , Milias-Argeitis Andreas , Khammash Mustafa
Published: May 2017

The study of gene expression at the single-cell level has exposed the importance of stochasticity for the behavior of cellular systems. Research on cellular variability has mostly relied on observing expression either in response to natural stimuli or to constant gene regulators. However, the ability to probe cells individually can lead to a deeper understanding of the underlying process. Here, we propose an experimental platform for optogenetic feedback control of individual cells. It consists of a digital micromirror device that, coupled to a microscope, can target light-responsive cells with individualized illumination profiles, thereby exploiting the good spatial resolution of optogenetic induction. Together with an automated software pipeline for segmentation, quantification and tracking of single cells, the platform enables independent and real-time control of numerous cells. We demonstrate our platform by regulating transcription in over a hundred yeast cells simultaneously, while achieving tunability of mRNA abundance. Using a novel technique to measure extrinsic variation, we further show that single cell feedback regulation of this highly stochastic process achieves a 10-fold reduction of extrinsic variation in nascent mRNA over population control, with superior control loop properties. Our platform establishes a new, flexible method for studying transcriptional dynamics in single cells.
Predicting ligand-dependent tumors from multi-dimensional signaling features
Authors: Hass Helge , Masson Kristina , Wohlgemuth Sibylle , Paragas Violette , Allen John E , Sevecka Mark , Pace Emily , Timmer Jens , Stelling Joerg , MacBeath Gavin , Schoeberl Birgit , Raue Andreas
Published: May 2017

Targeted therapies have shown significant patient benefit in about 5-10% of solid tumors that are addicted to a single oncogene. Here, we explore the idea of ligand addiction as a driver of tumor growth. High ligand levels in tumors have been shown to be associated with impaired patient survival, but targeted therapies have not yet shown great benefit in unselected patient populations. Using a novel approach of applying Bagged Decision Trees (BDT) to high-dimensional signaling features derived from a computational model, we can predict ligand dependent proliferation across a set of 58 cell lines. This mechanistic, multi-pathway model that features receptor heterodimerization, was trained on seven cancer cell lines and can predict signaling across two independent cell lines by adjusting only the receptor expression levels for each cell line. Interestingly, for patient samples the predicted tumor growth response correlates with high growth factor expression in the tumor microenvironment, which argues for a co-evolution of both factorsin vivo.

Prediction of ligand-induced growth of cancer cell lines, which correlates with ligand-blocking antibody efficacy, could be significantly improved by learning from features of a mechanistic signaling model, and was applied to reveal a correlation between growth factor expression and predicted response in patient samples.
Vaxrank: A computational tool for designing personalized cancer vaccines
Authors: Rubinsteyn Alexander , Hodes Isaac , Kodysh Julia , Hammerbacher Jeffrey
Published: May 2017

Therapeutic vaccines targeting mutant tumor antigens (“neoantigens”) are an increasingly popular form of personalized cancer immunotherapy. Vaxrank is a computational tool for selecting neoantigen vaccine peptides from tumor mutations, tumor RNA data, and patient HLA type. Vaxrank is freely available atwww.github.com/openvax/vaxrankunder the Apache 2.0 open source license and can also be installed from the Python Package Index.
Brain xQTL map: Integrating the genetic architecture of the human brain transcriptome and epigenome
Authors: Ng B , White CC , Klein H , Sieberts SK , McCabe C , Patrick E , Xu J , Yu L , Gaiteri C , Bennett DA , Mostafavi S , Jager PL De
Published: May 2017

We perform quantitative trait locus (xQTL) analyses on a multi-omic dataset, comprising RNA sequence, DNA methylation, and histone acetylation ChIP sequence data from the dorsolateral prefrontal cortex of 411 older adult individuals. We identify SNPs that are significantly associated with gene expression, DNA methylation, and histone modification levels. Many SNPs influence more than one type of molecular feature, and epigenetic features are shown to mediate eQTLs in a number of (9%) such loci. We illustrate the utility of our new resource,xQTL Serve, in prioritizing the cell type most affected by an xQTL and in enhancing genome wide association studies (GWAS) as we report 18 additional CNS disease susceptibility loci after re-analyzing published studies.
OCT4 impedes cell fate redirection by the melanocyte lineage master regulator MITF
Authors: Sheinboim Danna , Maza Itay , Dror Iris , Parikh Shivang , Krupalnik Vladislav , Bell Rachel E , Zviran Asaf , Suita Yusuke , Hakim Ofir , Gutfreund Yael Mandel , Khaled Mehdi , Hanna Jacob H , Levy Carmit
Published: May 2017

Ectopic expression of lineage master regulators induces transdifferentiation. Whether cell fate transitions can be induced during various developmental stages has never been systemically examined. Here we discovered that amongst different developmental stages, embryonic stem cells (ESCs) were resistant to cell fate conversion induced by the melanocyte lineage master regulator MITF. We generated a transgenic system and found that in ESCs, the pluripotency master regulator, OCT4, counteracts pro-differentiation induced by MITF by physical interference with MITF transcriptional activity. We further found that ESCs must be released from OCT4-maintained pluripotency prior to ectopically induced differentiation. Moreover, OCT4 induction in various differentiated cells repressed their lineage identity in vivo. Alongside, chromatin architecture combined with ChIP-seq analysis suggested that OCT4 competes with various lineage master regulators for binding promoters and enhancers. Our analysis reveals pluripotency and transdifferentiation regulatory principles and could open new opportunities in the field of regenerative medicine.
Enriched expression of genes associated with autism spectrum disorders in human inhibitory neurons
Authors: Wang Ping , Zhao Dejian , Lachman Herbert M. , Zheng Deyou
Published: May 2017

Autism spectrum disorder (ASD) is highly heritable but genetically heterogeneous. The affected neural circuits and cell types remain unclear and may vary at different developmental stages. By analyzing multiple sets of human single cell transcriptome profiles, we found that ASD candidates showed enriched gene expression in neurons, especially in inhibitory neurons. ASD candidates were also more likely to be the hubs of the co-expressed module that is highly expressed in inhibitory neurons, a feature not detected for excitatory neurons. In addition, we found that upregulated genes in multiple ASD cortex samples were also enriched with genes highly expressed in inhibitory neurons, suggesting a potential increase of inhibitory neurons and an imbalance in the ratio between excitatory and inhibitory neurons. Furthermore, the downstream targets of several ASD candidates, such asCHD8, EHMT1andSATB2,also displayed enriched expression in inhibitory neurons. Taken together, our analysis of single cell transcriptomic data suggest that inhibitory neurons may be the major neuron subtype affected by the disruption of ASD gene networks, providing single cell functional evidence to support the excitatory/inhibitory (E/I) imbalance hypothesis.
Forces driving cell sorting inHydra
Authors: Cochet-Escartin Olivier , Locke Tiffany T. , Shi Winnie H. , Steele Robert E. , Collins Eva-Maria S.
Published: May 2017

Cell sorting, whereby a heterogeneous cell mixture organizes into distinct tissues, is a fundamental patterning process in development. So far, most studies of cell sorting have relied either on 2-dimensional cellular aggregates,in vitrosituations that do not have a direct counterpartin vivo,or were focused on the properties of single cells. Here, we report the first multiscale experimental study on 3-dimensional regeneratingHydraaggregates, capable of reforming a full animal. By quantifying the kinematics of single cell and whole aggregate behaviors, we show that no differences in cell motility exist among cell types and that sorting dynamics follow a power law. Moreover, we measure the physical properties of separated tissues and determine their viscosities and surface tensions. Based on our experimental results and numerical simulations, we conclude that tissue interfacial tensions are sufficient to explainHydracell sorting. Doing so, we illustrate D’Arcy Thompson’s central idea that biological organization can be understood through physical principles, an idea which is currently re-shaping the field of developmental biology.

Summary statement

Hydraregenerates after dissociation into single cells. We show how physical mechanisms can explain the first step of regeneration, whereby ectodermal and endodermal cells sort out to form distinct tissue layers.
Deep transcriptome annotation suggests that small and large proteins encoded in the same genes often cooperate
Authors: Samandi Sondos , Roy Annie V. , Delcourt Vivian , Lucier Jean-François , Gagnon Jules , Beaudoin Maxime C. , Vanderperre Benoît , Breton Marc-André , Motard Julie , Jacques Jean-François , Brunelle Mylène , Gagnon-Arsenault Isabelle , Fournier Isabelle , Ouangraoua Aida , Hunting Darel J. , Cohen Alan A. , Landry Christian R. , Scott Michelle S. , Roucou Xavier
Published: May 2017

Recent studies in eukaryotes have demonstrated the translation of alternative open reading frames (altORFs) in addition to annotated protein coding sequences (CDSs). We show that a large number of small proteins could in fact be coded by altORFs. The putative alternative proteins translated from altORFs have orthologs in many species and evolutionary patterns indicate that altORFs are particularly constrained in CDSs that evolve slowly. Thousands of predicted alternative proteins are detected in proteomic datasets by reanalysis using a database containing predicted alternative proteins. Protein domains and co-conservation analyses suggest a potential functional relationship between small and large proteins encoded in the same genes. This is illustrated with specific examples, including altMiD51, a 70 amino acid mitochondrial fission-promoting protein encoded inMiD51/Mief1/SMCR7L, a gene encoding an annotated protein promoting mitochondrial fission. Our results suggest that many coding genes code for more than one protein that are often functionally related.
Rapid feedback responses are flexibly coordinated across arm muscles to support goal-directed reaching
Authors: Weiler Jeffrey , Gribble Paul L. , Pruszynski J. Andrew
Published: May 2017

A transcortical pathway helps support goal-directed reaching by processing somatosensory information to produce rapid feedback responses across multiple joints and muscles. Here we tested whether such feedback responses can account for changes in arm configuration and for arbitrary visuomotor transformations – two manipulations that alter how muscles at the elbow and wrist need to be coordinated to achieve task success. Participants used a planar three degree-of-freedom exoskeleton robot to move a cursor to a target following a mechanical perturbation that flexed the elbow. In our first experiment, the cursor was mapped to the veridical position of the robot handle, but participants grasped the handle with two different hand orientations (thumb pointing upward or thumb point downward). We found that large rapid feedback responses were evoked in wrist extensor muscles when wrist extension helped move the cursor to the target (i.e., thumb upward), and in wrist flexor muscles when wrist flexion helped move the cursor to the target (i.e., thumb downward). In our second experiment, participants grasped the robot handle with their thumb pointing upward, but the cursor’s movement was either veridical, or was mirrored such that flexing the wrist moved the cursor as if the participant extended their wrist, and vice versa. After extensive practice, we found that rapid feedback responses were appropriately tuned to the wrist muscles that supported moving the cursor to the target when the cursor was mapped to the mirrored movement of the wrist, but were not tuned to the appropriate wrist muscles when the cursor was remapped to the wrist’s veridical movement.

New and Noteworthy

We show that rapid feedback responses were evoked in different wrist muscles depending on the arm’s orientation, and this muscle activity was appropriate to generate the wrist motion that supported a reaching action. Notably, we also show that these rapid feedback responses can be evoked in wrist muscles that are detrimental to a reaching action if a non-veridical mapping between wrist and hand motion is extensively learned.
Murine glomerular transcriptome links endothelial cell-specific molecule-1 deficiency with susceptibility to diabetic nephropathy
Authors: Zheng Xiaoyi , Soroush Fariborz , Long Jin , Hall Evan T. , Adishesha Puneeth K. , Bhattacharya Sanchita , Kiani Mohammad F. , Bhalla Vivek
Published: May 2017

Diabetic nephropathy (DN) is the leading cause of kidney disease; however, there are no early biomarkers and no cure. Thus, there is a large unmet need to predict which individuals will develop nephropathy and to understand the molecular mechanisms which govern this susceptibility. We compared the glomerular transcriptome from mice with distinct susceptibilities to DN, and identified differential regulation of genes that modulate inflammation. From these genes, we identified endothelial cell specific molecule-1 (Esm-1), as a glomerular-enriched determinant of resistance to DN. Glomerular Esm-1 mRNA and protein were lower in DN-susceptible, DBA/2, compared to DN-resistant, C57BL/6, mice. We demonstrated higher Esm-1 secretion from primary glomerular cultures of diabetic mice, and high glucose was sufficient to increase Esm-1 mRNA and protein secretion in both strains of mice. However, induction was significantly attenuated in DN-susceptible mice. Urine Esm-1 was also significantly higher only in DN-resistant mice. Moreover, using intravital microscopy and a biomimetic microfluidic assay, we showed that Esm-1 inhibited rolling and transmigration in a dose-dependent manner. For the first time we have uncovered glomerular-derived Esm-1 as a potential non-invasive biomarker of DN. Esm-1 inversely correlates with disease susceptibility and inhibits leukocyte infiltration, a critical factor in protecting the kidney from DN.
An Experiment in Learning the Language of Sequence Motifs: Sequence Logos vs. Finite-State Machines
Authors: Francisco Alexandre P , Gagie Travis , Kempa Dominik , Salmela Leena , Sverdlov Sophie , Toivonen Jarkko , Ukkonen Esko
Published: May 2017

Position weight matrices (PWMs) are the standard way to model binding site affinities in bioinformatics. However, they assume that symbol occurrences are position independent and, hence, they do not take into account symbols co-occurrence at different sequence positions. To address this problem, we propose to construct finite-state machines (FSMs) instead. A modified version of the Evidence-Driven State Merging (EDSM) heuristic is used to reduce the number of states as FSMs grow too quickly as a function of the number of sequences to reveal any useful structure. We tested our approach on sequence data for the transcription factor HNF4 and found out that the constructed FSMs provide small representations and an intuitive visualization. Furthermore, the FSM was better than PWMs at discriminating the positive and negative sequences in our data set.
OMSV enables accurate and comprehensive identification of large structural variations from nanochannel-based single-molecule optical maps
Authors: Li Le , Kwok Tsz-Piu , Leung Alden King-Yung , Lai Yvonne Y. Y. , Pang Iris K. , Chung Grace Tin-Yun , Mak Angel C. Y. , Poon Annie , Chu Catherine , Li Menglu , Wu Jacob J. K. , Lam Ernest T. , Cao Han , Lin Chin , Sibert Justin , Yiu Siu-Ming , Xiao Ming , Lo Kwok-Wai , Kwok Pui-Yan , Chan Ting-Fung , Yip Kevin Y.
Published: May 2017

Human genomes contain structural variations (SVs) that are associated with various phenotypic variations and diseases. SV detection by sequencing is incomplete due to limited read length. Nanochannel-based optical mapping (OM) allows direct observation of SVs up to hundreds of kilo-bases in size on individual DNA molecules, making it a promising alternative technology for identifying large SVs. SV detection from optical maps is non-trivial due to complex types of error present in OM data, and no existing methods can simultaneously handle all these complex errors and the wide spectrum of SV types. Here we present a novel method, OMSV, for accurate and comprehensive identification of SVs from optical maps. OMSV detects both homozygous and heterozygous SVs, SVs of various types and sizes, and SVs with and without creating/destroying restriction sites. In an extensive series of tests based on real and simulated data, OMSV achieved both high sensitivity and specificity, with clear performance gains over the latest existing method. Applying OMSV to a human cell line, we identified hundreds of SVs >2kbp, with 65% of them missed by sequencing-based callers. Independent experimental validations confirmed the high accuracy of these SVs. We also demonstrate how OMSV can incorporate sequencing data to determine precise SV break points and novel sequences in the SVs not contained in the reference. We provide OMSV as open-source software to facilitate systematic studies of large SVs.