bluuebunny/crossref_metadata_2025 huggingface dataset:
Challenges and needs in experimental therapies for multiple sclerosis
Authors: Lutterotti Andreas
Published: April 2018

Purpose of review

Despite dramatic advances in the treatment of people with multiple sclerosis over the last decade, several unmet medical needs still remain and should be approached with new compounds in experimental clinical trials. The prerequisites for successful clinical trials in multiple sclerosis have changed considerably over time and activities have started to improve clinical development of new drugs in several aspects including trial designs, patient selection and outcome parameters. This review will address some of the challenges in early experimental trials in multiple sclerosis and recent approaches in the field.

Recent findings

Highly intensive treatment regimens like autologous hematopoietic stem cell transplantation provide evidence for sustained long-term treatment effects in multiple sclerosis patients. Several different approaches towards neuroprotection and remyelination have entered the clinical phase and demonstrated that stabilization, even improvement of disability is achievable in short-term studies.

New therapeutic strategies have entered the clinic with the prospects of long-term efficacy and enduring effects on disability progression.
Genetic Survey of Adult-Onset Idiopathic Intracranial Hypertension
Authors: Kuehn Markus H. , Mishra Rajashree , Deonovic Benjamin E. , Miller Kimberly N. , McCormack Shana E. , Liu Grant T. , Kupersmith Mark J. , Wall Michael ,   the NORDIC IIHTT Study Group
Published: April 2018

Background:

Idiopathic intracranial hypertension (IIH) is a condition characterized by increased intracranial pressure of unknown cause. IIH has been shown to be associated with female sex as well as obesity. This genome-wide association study was performed to determine whether genetic variants are associated with this condition.

Methods:

We analyzed the chromosomal DNA of 95 patients with IIH enrolled in the Idiopathic Intracranial Hypertension Treatment Trial and 95 controls matched on sex, body mass index, and self-reported ethnicity. The samples were genotyped using Illumina Infinium HumanCoreExome v1-0 array and analyzed using a generalized linear mixed model that accounted for population stratification using multidimensional scaling.

Results:

A total of 301,908 single nucleotide polymorphisms (SNPs) were evaluated. The strongest associations observed were for rs2234671 on chromosome 2 (P = 4.93 × 10−07), rs79642714 on chromosome 6 (P = 2.12 × 10−07), and rs200288366 on chromosome 12 (P = 6.23 × 10−07). In addition, 3 candidate regions marked by multiple associated SNPs were identified on chromosome 5, 13, and 14.

Conclusions:

This is the first study to investigate the genetics of IIH in a rigorously characterized cohort. The study was limited by its modest size and thus would have only been able to demonstrate highly significant association on a genome-wide scale for relatively common alleles exerting large effects. However, several variants and loci were identified that might be strong candidates for follow-up studies in other well-phenotyped cohorts.
Negative emissions technologies and carbon capture and storage to achieve the Paris Agreement commitments
Authors: Haszeldine R. Stuart , Flude Stephanie , Johnson Gareth , Scott Vivian
Published: April 2018

How will the global atmosphere and climate be protected? Achieving net-zero CO
2
emissions will require carbon capture and storage (CCS) to reduce current GHG emission rates, and negative emissions technology (NET) to recapture previously emitted greenhouse gases. Delivering NET requires radical cost and regulatory innovation to impact on climate mitigation. Present NET exemplars are few, are at small-scale and not deployable within a decade, with the exception of rock weathering, or direct injection of CO
2
into selected ocean water masses. To keep warming less than 2°C, bioenergy with CCS (BECCS) has been modelled but does not yet exist at industrial scale. CCS already exists in many forms and at low cost. However, CCS has no political drivers to enforce its deployment. We make a new analysis of all global CCS projects and model the build rate out to 2050, deducing this is 100 times too slow. Our projection to 2050 captures just 700 Mt CO
2
 yr
−1
, not the minimum 6000 Mt CO
2
 yr
−1
required to meet the 2°C target. Hence new policies are needed to incentivize commercial CCS. A first urgent action for all countries is to commercially assess their CO
2
storage. A second simple action is to assign a Certificate of CO
2
Storage onto producers of fossil carbon, mandating a progressively increasing proportion of CO
2
to be stored. No CCS means no 2°C.

This article is part of the theme issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels'.
Climate extremes, land–climate feedbacks and land-use forcing at 1.5°C
Authors: Seneviratne Sonia I. , Wartenburger Richard , Guillod Benoit P. , Hirsch Annette L. , Vogel Martha M. , Brovkin Victor , van Vuuren Detlef P. , Schaller Nathalie , Boysen Lena , Calvin Katherine V. , Doelman Jonathan , Greve Peter , Havlik Petr , Humpenöder Florian , Krisztin Tamas , Mitchell Daniel , Popp Alexander , Riahi Keywan , Rogelj Joeri , Schleussner Carl-Friedrich , Sillmann Jana , Stehfest Elke
Published: April 2018

This article investigates projected changes in temperature and water cycle extremes at 1.5°C of global warming, and highlights the role of land processes and land-use changes (LUCs) for these projections. We provide new comparisons of changes in climate at 1.5°C versus 2°C based on empirical sampling analyses of transient simulations versus simulations from the ‘Half a degree Additional warming, Prognosis and Projected Impacts’ (HAPPI) multi-model experiment. The two approaches yield similar overall results regarding changes in climate extremes on land, and reveal a substantial difference in the occurrence of regional extremes at 1.5°C versus 2°C. Land processes mediated through soil moisture feedbacks and land-use forcing play a major role for projected changes in extremes at 1.5°C in most mid-latitude regions, including densely populated areas in North America, Europe and Asia. This has important implications for low-emissions scenarios derived from integrated assessment models (IAMs), which include major LUCs in ambitious mitigation pathways (e.g. associated with increased bioenergy use), but are also shown to differ in the simulated LUC patterns. Biogeophysical effects from LUCs are not considered in the development of IAM scenarios, but play an important role for projected regional changes in climate extremes, and are thus of high relevance for sustainable development pathways.

This article is part of the theme issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels'.
Pathways limiting warming to 1.5°C: a tale of turning around in no time?
Authors: Kriegler Elmar , Luderer Gunnar , Bauer Nico , Baumstark Lavinia , Fujimori Shinichiro , Popp Alexander , Rogelj Joeri , Strefler Jessica , van Vuuren Detlef P.
Published: April 2018

We explore the feasibility of limiting global warming to 1.5°C without overshoot and without the deployment of carbon dioxide removal (CDR) technologies. For this purpose, we perform a sensitivity analysis of four generic emissions reduction measures to identify a lower bound on future CO2emissions from fossil fuel combustion and industrial processes. Final energy demand reductions and electrification of energy end uses as well as decarbonization of electricity and non-electric energy supply are all considered. We find the lower bound of cumulative fossil fuel and industry CO2emissions to be 570 GtCO2for the period 2016–2100, around 250 GtCO2lower than the lower end of available 1.5°C mitigation pathways generated with integrated assessment models. Estimates of 1.5°C-consistent CO2budgets are highly uncertain and range between 100 and 900 GtCO2from 2016 onwards. Based on our sensitivity analysis, limiting warming to 1.5°C will require CDR or terrestrial net carbon uptake if 1.5°C-consistent budgets are smaller than 650 GtCO2. The earlier CDR is deployed, the more it neutralizes post-2020 emissions rather than producing net negative emissions. Nevertheless, if the 1.5°C budget is smaller than 550 GtCO2, temporary overshoot of the 1.5°C limit becomes unavoidable if CDR cannot be ramped up faster than to 4 GtCO2in 2040 and 10 GtCO2in 2050.

This article is part of the theme issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels’.
Towards legitimacy of the solar geoengineering research enterprise
Authors: Frumhoff Peter C. , Stephens Jennie C.
Published: April 2018

Mounting evidence that even aggressive reductions in net emissions of greenhouse gases will be insufficient to limit global climate risks is increasing calls for atmospheric experiments to better understand the risks and implications of also deploying solar geoengineering technologies to reflect sunlight and rapidly lower surface temperatures. But solar geoengineering research itself poses significant environmental and geopolitical risks. Given limited societal awareness and public dialogue about this climate response option, conducting such experiments without meaningful societal engagement could galvanize opposition to solar geoengineering research from civil society, including the most climate vulnerable communities who are among its intended beneficiaries. Here, we explore whether and how a solar geoengineering research enterprise might be developed in a way that promotes legitimacy as well as scientific credibility and policy relevance. We highlight the distinctive responsibilities of researchers and research funders to ensure that solar geoengineering research proposals are subject to legitimate societal review and scrutiny, recommend steps they can take to strive towards legitimacy and call on them to be explicitly open to multiple potential outcomes, including the societal rejection or considerable alteration of the solar geoengineering research enterprise.

This article is part of the theme issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels'.
Reaching a 1.5°C target: socio-technical challenges for a rapid transition to low-carbon electricity systems
Authors: Eyre Nick , Darby Sarah J. , Grünewald Philipp , McKenna Eoghan , Ford Rebecca
Published: April 2018

A 1.5°C global average target implies that we should no longer focus on merely incremental emissions reductions from the electricity system, but rather on fundamentally re-envisaging a system that, sooner rather than later, becomes carbon free. Many low-carbon technologies are surpassing mainstream predictions for both uptake and cost reduction. Their deployment is beginning to be disruptive within established systems. ‘Smart technologies’ are being developed to address emerging challenges of system integration, but their rates of future deployment remain uncertain. We argue that transition towards a system that can fully displace carbon generation sources will require expanding the focus of our efforts beyond technical solutions. Recognizing that change has social and technical dimensions, and that these interact strongly, we set out a socio-technical review that covers electricity infrastructure, citizens, business models and governance. It describes some of the socio-technical challenges that need to be addressed for the successful transition of the existing electricity systems. We conclude that a socio-technical understanding of electricity system transitions offers new and better insights into the potential and challenges for rapid decarbonization.

This article is part of the theme issue ‘The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels'.
Sequential regulation of maternal mRNAs through a conserved cis-acting element in their 3’UTRs
Authors: Flora Pooja , Wong-Deyrup Siu Wah , Martin Elliot Todd , Palumbo Ryan J , Nasrallah Mohamad , Oligney Andrew , Blatt Patrick , Patel Dhruv , Fuchs Gabriele , Rangan Prashanth
Published: April 2018

Maternal mRNAs are synthesized during oogenesis to initiate the development of future generations. Some maternal mRNAs are determinants of somatic or germline fate and must be translationally repressed until embryogenesis. However, the translational repressors themselves are also temporally regulated. We usepolar granule component(pgc), aDrosophilamaternal mRNA, as a model system to ask how maternal mRNAs are repressed while the regulatory landscape is continually shifting.pgc, a potent transcriptional silencer and germline determinant, is translationally regulated throughout oogenesis. We find that the 3’UTR ofpgcmRNA contains a conserved ten-nucleotide sequence that is bound by different conserved RNA binding proteins (RBPs) at different stages of oogenesis to continuously repress translation except for a brief expression in the stem cell daughter. Pumilio (Pum) binds to this sequence in undifferentiated and early differentiating oocytes and recruits other temporally restricted translational regulators to blockpgctranslation. After differentiation, Pum levels diminish and Bruno (Bru) levels increase, allowing Bru to bind the same 3’UTR sequence and take over translational repression ofpgcmRNA. We have identified a class of maternal mRNAs regulated during oogenesis by both Pum and Bru, includingZelda, activator of the zygotic genome, which contain this core 10-nt regulatory sequence. Our data suggests that this hand off mechanism is more generally utilized to inhibit translation of maternal mRNAs during oogenesis.
The CoLoMoTo Interactive Notebook: Accessible and Reproducible Computational Analyses for Qualitative Biological Networks
Authors: Naldi Aurélien , Hernandez Céline , Levy Nicolas , Stoll Gautier , Monteiro Pedro T. , Chaouiya Claudine , Helikar Tomáš , Zinovyev Andrei , Calzone Laurence , Cohen-Boulakia Sarah , Thieffry Denis , Paulevé Loïc
Published: April 2018

Analysing models of biological networks typically relies on workflows in which different software tools with sensitive parameters are chained together, many times with additional manual steps. The accessibility and reproducibility of such workflows is challenging, as publications often overlook analysis details, and because some of these tools may be difficult to install, and/or have a steep learning curve. The CoLoMoTo Interactive Notebook provides a unified environment to edit, execute, share, and reproduce analyses of qualitative models of biological networks. This framework combines the power of different technologies to ensure repeatability and to reduce users’ learning curve of these technologies. The framework is distributed as a Docker image with the tools ready to be run without any installation step besides Docker, and is available on Linux, macOS, and Microsoft Windows. The embedded computational workflows are edited with a Jupyter web interface, enabling the inclusion of textual annotations, along with the explicit code to execute, as well as the visualisation of the results. The resulting notebook files can then be shared and re-executed in the same environment. To date, the CoLoMoTo Interactive Notebook provides access to software tools including GINsim, BioLQM, Pint, MaBoSS, and Cell Collective for the modelling and analysis of Boolean and multi-valued networks. More tools will be included in the future. We developed a Python interface for each of these tools to offer a seamless integration in the Jupyter web interface and ease the chaining of complementary analyses.
Gamma synchronization between V1 and V4 improves behavioral performance
Authors: Rohenkohl Gustavo , Bosman Conrado Arturo , Fries Pascal
Published: April 2018

Motor behavior is often driven by visual stimuli, relying on efficient feedforward communication from lower to higher visual areas. The Communication-through-Coherence hypothesis proposes that interareal communication depends on coherence at an optimal phase relation. While previous studies have linked effective communication to enhanced interareal coherence, it remains unclear, whether this interareal coherence occurs at an optimal phase relation that actually improves the stimulus transmission to behavioral report. We recorded local field potentials simultaneously from areas V1 and V4 of macaque monkeys performing a selective visual attention task, during which they reported changes of the attended stimulus. Gamma synchronization between V1 and V4, immediately preceding the stimulus change, predicted subsequent reaction times (RTs). Crucially, RTs were systematically slowed as trial-by-trial interareal gamma phase relations deviated from the phase relation at which V1 and V4 synchronized on average. These effects were specific to the attended stimulus and not due to local power or phase inside V1 or V4. We conclude that interareal gamma synchronization occurs at the optimal phase relation and thereby improves interareal communication and the effective transformation of sensory inputs into motor responses.
Sparse recurrent excitatory connectivity in the microcircuit of the adult mouse and human cortex
Authors: Seeman Stephanie C. , Campagnola Luke , Davoudian Pasha A. , Hoggarth Alex , Hage Travis A. , Bosma-Moody Alice , Baker Christopher A. , Lee Jung Hoon , Mihalas Stefan , Teeter Corinne , Ko Andrew L. , Ojemann Jeffrey G. , Gwinn Ryder P. , Silbergeld Daniel L. , Cobbs Charles , Phillips John , Lein Ed , Murphy Gabe J. , Koch Christof , Zeng Hongkui , Jarsky Tim
Published: April 2018

Generating a comprehensive description of cortical networks requires a large-scale, systematic approach. To that end, the Allen Institute is engaged in a pipeline project using multipatch electrophysiology, supplemented with 2-photon optogenetics, to characterize connectivity and synaptic signaling between classes of neurons in adult mouse and human cortex. We focus on producing results detailed enough for the generation of computational models and enabling comparison with future studies. Here we report our examination of intralaminar connectivity within each of several classes of excitatory neurons. We find that connections are sparse but present among all excitatory cell types and layers we sampled, with the most sparse connections in layers 5 and 6. Almost all mouse synapses exhibited short-term depression with similar dynamics. Synaptic signaling between a subset of layer 2/3 neurons; however, exhibited facilitation. These results contribute to a body of evidence describing recurrent excitatory connectivity as a conserved feature of cortical microcircuits.
Deep Learning Global Glomerulosclerosis in Transplant Kidney Frozen Sections
Authors: Marsh Jon N. , Matlock Matthew K. , Kudose Satoru , Liu Ta-Chiang , Stappenbeck Thaddeus S. , Gaut Joseph P. , Swamidass S. Joshua
Published: April 2018

Transplantable kidneys are in very limited supply. Accurate viability assessment prior to transplantation could minimize organ discard. Rapid and accurate evaluation of intra-operative donor kidney biopsies is essential for determining which kidneys are eligible for transplantation. The criteria for accepting or rejecting donor kidneys relies heavily on pathologist determination of the percent of glomeruli (determined from a frozen section) that are normal and sclerotic. This percentage is a critical measurement that correlates with transplant outcome. Inter- and intra-observer variability in donor biopsy evaluation is, however, significant. An automated method for determination of percent global glomerulosclerosis could prove useful in decreasing evaluation variability, increasing throughput, and easing the burden on pathologists. Here, we describe the development of a deep learning model that identifies and classifies non-sclerosed and sclerosed glomeruli in whole-slide images of donor kidney frozen section biopsies. This model extends a convolutional neural network (CNN) pre-trained on a large database of digital images. The extended model, when trained on just 48 whole slide images, exhibits slide-level evaluation performance on par with expert renal pathologists. The model substantially outperforms a model trained on image patches of isolated glomeruli. Encouragingly, the model’s performance is robust to slide preparation artifacts associated with frozen section preparation. As the first model reported that identifies and classifies normal and sclerotic glomeruli in frozen kidney sections, and thus the first model reported in the literature relevant to kidney transplantation, it may become an essential part of donor kidney biopsy evaluation in the clinical setting.
Association mapping identified novel candidate loci affecting wood formation in Norway spruce
Authors: Baison John , Vidalis Amarylis , Zhou Linghua , Chen Zhi-Qiang , Li Zitong , Sillanpää Mikko J , Bernahrdsson Carolina , Scofield Douglas G , Forsberg Nils , Olsson Lars , Karlsson Bo , Wu Harry , Ingvarsson Pär K , Lundqvist Sven-Olof , Niittylä Totte , Garcia Gil Rosario M
Published: April 2018

Norway spruce (Picea abies) is an important boreal forest tree species of significant ecological and economic importance. Hence there is a strong imperative to dissect the genetics controlling important wood quality traits in Norway spruce. We performed a functional genome-wide association mapping of 17 wood quality traits in Norway spruce using 178101 single-nucleotide polymorphisms (SNPs) generated from exome genotyping of 517 mother trees. The wood quality traits were defined using functional modelling of wood properties across annual growth rings. Association mapping was performed using a multilocus LASSO penalized regression method and we detected a total of 51 significant SNPs from 39 candidate genes that are involved in wood formation. Our study represents the first functional multi-locus genome-wide association mapping (AM) in Norway spruce. The results advance our understanding of the genetics influencing wood traits, identify novel candidate genes for further functional studies and support current Norway spruce breeding efforts.
A continental system for forecasting bird migration
Authors: Van Doren Benjamin M. , Horton Kyle G.
Published: April 2018

Billions of animals cross the globe each year during seasonal migrations, but efforts to monitor them are hampered by the irregularity and relative unpredictability of their movements. We developed a bird migration forecast system with continental scope by leveraging 23 years of spring observations to learn associations between atmospheric conditions and bird migration intensity. Our models explained up to 81% of variation in migration intensity across the United States at altitudes of 0-3000 m, and performance remained high when forecasting events 24-72 h into the future (68-72% variation explained). We infer that avian migratory movements across the United States frequently exceed 200 million individuals per night and exceed 500 million individuals per night during peak passage. Accurately forecasting bird migration will allow stakeholders to reduce collisions with illuminated buildings, airplanes, and wind turbines, predict movements under climate change scenarios, and engage the public.
Multimodal Hippocampal Subfield Grading For Alzheimer’s Disease Classification
Authors: Hett Kilian , Ta Vinh-Thong , Catheline Gwenaëlle , Tourdias Thomas , Manjón José V. , Coupé Pierrick ,   Alzheimer’s Disease Neuroimaging Initiative
Published: April 2018

Numerous studies have proposed biomarkers based on magnetic resonance imaging (MRI) to detect and predict the risk of evolution toward Alzheimer’s disease (AD). While anatomical MRI captures structural alterations, studies demonstrated the ability of diffusion MRI to capture microstructural modifications at an earlier stage. Several methods have focused on hippocampus structure to detect AD. To date, the patch-based grading framework provides the best biomarker based on the hippocampus. However, this structure is complex since the hippocampus is divided into several heterogeneous subfields not equally impacted by AD. Former in-vivo imaging studies only investigated structural alterations of these subfields using volumetric measurements and microstructural modifications with mean diffusivity measurements. The aim of our work is to study the efficiency of hippocampal subfields compared to the whole hippocampus structure with a multimodal patch-based framework that enables to capture subtler structural and microstructural alterations. To this end, we analyze the significance of the different hippocampal subfields for AD diagnosis and prognosis with volumetric, diffusivity measurements and a novel multimodal patch-based grading framework that combines structural and diffusion MRI. The experiments conducted in this work showed that the whole hippocampus provides the most discriminant biomarkers for advanced AD detection while biomarkers applied into subiculum obtain the best results for AD prediction, improving by 2% the accuracy compared to the whole hippocampus.
Consumption of carotenoids not increased by bacterial infection in brown trout embryos (Salmo trutta)
Authors: Marques da Cunha Lucas , Wilkins Laetitia G. E. , Menin Laure , Ortiz Daniel , Vocat-Mottier Véronique , Wedekind Claus
Published: April 2018

Carotenoids are organic pigment molecules that play important roles in signalling, control of oxidative stress, and immunity. Fish allocate carotenoids to their eggs, which gives them the typical yellow to red colouration and supports their resistance against microbial infections. However, it is still unclear whether carotenoids act mainly as a shield against infection or are used up during the embryos’ immune defence. We investigated this question with experimental families produced from wild-caught brown trout (Salmo trutta). Singly raised embryos were either exposed to the bacterial pathogen Pseudomonas fluorescens or sham-treated at one of two stages during their development. A previous study on these experimental families reported positive effects of egg carotenoids on embryo growth and resistance against the infection. Here, we quantified carotenoid consumption in these infected and sham-infected maternal sib groups. We found that carotenoid contents mostly decreased during embryogenesis. However, these decreases were neither linked to the virulence induced by the pathogen nor dependent on the time point of infection. We conclude that egg carotenoids are not significantly used up by the embryos’ immune defence.
RobusTAD: A Tool for Robust Annotation of Topologically Associating Domain Boundaries
Authors: Dali Rola , Bourque Guillaume , Blanchette Mathieu
Published: April 2018

Motivation

Topologically Associating Domains (TADs) are chromatin structures that can be identified by analysis of Hi-C data. Tools currently available for TAD identification are sensitive to experimental conditions such as coverage, resolution and noise level.

Results

Here, we present RobusTAD, a tool to score TAD boundaries in a manner that is robust to these parameters. In doing so, RobusTAD eases comparative analysis of TAD structures across multiple heterogeneous samples.

Availability

RobusTAD is implemented in R and released under a GPL license. RobusTAD can be downloaded from https://github.com/rdali/RobusTAD and runs on any standard desktop computer.

Contact

rola.dali@mail.mcgill.ca, blanchem@cs.mcgill.ca

Supplementary information

Supplementary data are available at Bioinformatics online.
Knockdown of GAS5 restores ox-LDL-induced impaired autophagy flux via upregulating miR-26a in human endothelial cells
Authors: Liang Weijie , Fan Taibing , Liu Lin , Zhang Lianzhong
Published: April 2018

Background

Oxidized low-density lipoprotein (ox-LDL)-induced endothelial cell (EC) injury and autophagy dysfunction play a vital role in the development of atherosclerosis. LncRNAs have been identified to participate in the regulation of pathogenesis of atherosclerosis. However, it remains largely undefined whether growth-arrest specific transcript 5 (GAS5) could influence ox-LDL-induced autophagy dysfunction in ECs.

Methods

The expressions of GAS5 and miR-26a in the plasma samples of patients with atherosclerosis and ox-LDL-treated human aortic endothelial cells (HAECs) were detected by qRT-PCR. Luciferase reporter assay, RNA immunoprecipitation (RIP), and RNA pull down were performed to validate whether GAS5 could directly interact with miR-26a. The effects of ox-LDL, GAS5 or combined with miR-26a on apoptosis and autophagy were evaluated by flow cytometry analysis and western blot, respectively.

Results

GAS5 expression was upregulated and miR-26a was downregulated in the plasma samples of patients with atherosclerosis and ox-LDL-treated HAECs. There was reciprocal inhibition between GAS5 and miR-26a expressions in ox-LDL-treated HAECs. We further demonstrated that GAS5 directly interacted with miR-26a in ox-LDL-treated HAECs. Additionally, ox-LDL administration induced apoptosis and impaired autophagy flux in HAECs. Rescue experiments demonstrated that GAS5 knockdown restored ox-LDL-induced impaired autophagy flux by upregulating miR-26a in HAECs.

Conclusion

Knockdown of GAS5 restores ox-LDL-induced impaired autophagy flux via upregulating miR-26a in human endothelial cells, revealing a novel regulatory mechanism for ox-LDL-induced impaired autophagy flux in ECs through ceRNA crosstalk.
Accounting for programmed ribosomal frameshifting in the computation of codon
Authors: Garcia Victor , Zoller Stefan , Anisimova Maria
Published: April 2018

Experimental evidence shows that synonymous mutations can have important consequences on genetic fitness. Many organisms displaycodon usage bias(CUB), where synonymous codons that are translated into the same amino acid appear with distinct frequency. CUB is thought to arise from selection for translational efficiency and accuracy, termed thetranslational efficiency hypothesis(TEH). Indeed, CUB indices correlate with protein expression levels, which is widely interpreted as evidence for translational selection. However, these tests neglect −1 programmed ribosomal frameshifting (−1 PRF), an important translational disruption effect found across all organisms of the tree of life. Genes that contain −1 PRF signals should cost more to express than genes without. Thus, CUB indices that do not consider −1 PRF may overestimate genes’ true adaptation to translational efficiency and accuracy constraints. Here, we first investigate whether −1 PRF signals do indeed carry such translational cost. We then propose two corrections for CUB indices for genes containing −1 PRF signals. We retest the TEH under these corrections. We find that the correlation between corrected CUB index and protein expression remains intact for most levels of uniform −1 PRF efficiencies, and tends to increase when these efficiencies decline with protein expression. We conclude that the TEH is strengthened and that −1 PRF events constitute a promising and useful tool to examine the relationships between CUB and selection for translation efficiency and accuracy.
Collective feature selection to identify crucial epistatic variants
Authors: Verma Shefali S. , Lucas Anastasia , Zhang Xinyuan , Veturi Yogasudha , Dudek Scott , Li Binglan , Li Ruowang , Urbanowicz Ryan , Moore Jason H. , Kim Dokyoon , Ritchie Marylyn D.
Published: April 2018

Background

Machine learning methods have gained popularity and practicality in identifying linear and non-linear effects of variants associated with complex disease/traits. Detection of epistatic interactions still remains a challenge due to the large number of features and relatively small sample size as input, thus leading to the so-called “short fat data” problem. The efficiency of machine learning methods can be increased by limiting the number of input features. Thus, it is very important to perform variable selection before searching for epistasis. Many methods have been evaluated and proposed to perform feature selection, but no single method works best in all scenarios. We demonstrate this by conducting two separate simulation analyses to evaluate the proposed collective feature selection approach.

Results

Through our simulation study we propose a collective feature selection approach to select features that are in the “union” of the best performing methods. We explored various parametric, non-parametric, and data mining approaches to perform feature selection. We choose our top performing methods to select the union of the resulting variables based on a user-defined percentage of variants selected from each method to take to downstream analysis. Our simulation analysis shows that non-parametric data mining approaches, such as MDR, may work best under one simulation criteria for the high effect size (penetrance) datasets, while non-parametric methods designed for feature selection, such as Ranger and Gradient boosting, work best under other simulation criteria. Thus, using a collective approach proves to be more beneficial for selecting variables with epistatic effects also in low effect size datasets and different genetic architectures. Following this, we applied our proposed collective feature selection approach to select the top 1% of variables to identify potential interacting variables associated with Body Mass Index (BMI) in ~44,000 samples obtained from Geisinger’s MyCode Community Health Initiative (on behalf of DiscovEHR collaboration).

Conclusions

In this study, we were able to show that selecting variables using a collective feature selection approach could help in selecting true positive epistatic variables more frequently than applying any single method for feature selection via simulation studies. We were able to demonstrate the effectiveness of collective feature selection along with a comparison of many methods in our simulation analysis. We also applied our method to identify non-linear networks associated with obesity.
Weakly Supervised Learning of Single-Cell Feature Embeddings
Authors: Caicedo Juan C. , McQuin Claire , Goodman Allen , Singh Shantanu , Carpenter Anne E.
Published: April 2018

We study the problem of learning representations for single cells in microscopy images to discover biological relationships between their experimental conditions. Many new applications in drug discovery and functional genomics require capturing the morphology of individual cells as comprehensively as possible. Deep convolutional neural networks (CNNs) can learn powerful visual representations, but require ground truth for training; this is rarely available in biomedical profiling experiments. While we do not know which experimental treatments produce cells that look alike, we do know that cells exposed to the same experimental treatment should generally look similar. Thus, we explore training CNNs using a weakly supervised approach that uses this information for feature learning. In addition, the training stage is regularized to control for unwanted variations using mixup or RNNs. We conduct experiments on two different datasets; the proposed approach yields single-cell embeddings that are more accurate than the widely adopted classical features, and are competitive with previously proposed transfer learning approaches.
Using citizen science data in integrated population models to inform conservation decision-making
Authors: Robinson Orin J , Ruiz-Gutierrez Viviana , Fink Daniel , Meese Robert J , Holyoak Marcel , Cooch Evan G
Published: April 2018

Analysis of animal population status and change are core elements of ecological research and critical for prioritizing conservation actions. Traditionally, count-based data from structured surveys have been the main source of information used to estimate trends and changes in populations. In the past decade, advances in integrated population models (IPMs) have allowed these data to be combined with other data sources (e.g., observations of marked individuals). IPMs have allowed researchers to determine the direction and magnitude of a species' population trajectory and to test underlying mechanisms. For many species, life-history characteristics (e.g., low site-fidelity), low abundance and/or low detection probability make it difficult to collect sufficient data; thus, IPMs for these species are difficult to employ. We used count data from eBird to estimate population trends for one such species, the tricolored blackbird (Agelaius tricolor). We combined estimates of relative abundance with banding and nesting data. Our joint estimation of demographic rates allowed us to evaluate their individual contributions to the population growth rate. We suggest that investments in increasing reproductive success and recruitment are the most likely conservation strategies to increase the population. The extensive survey efforts of citizen scientists aided the employment of IPMs to inform conservation efforts.
Animal models of chemotherapy-induced peripheral neuropathy: a machine-assisted systematic review and meta-analysis
Authors: Currie Gillian L. , Angel-Scott Helena N. , Colvin Lesley , Cramond Fala , Hair Kaitlyn , Khandoker Laila , Liao Jing , Macleod Malcolm , McCann Sarah K. , Morland Rosie , Sherratt Nicki , Stewart Robert , Tanriver-Ayder Ezgi , Thomas James , Wang Qianying , Wodarski Rachel , Xiong Ran , Rice Andrew S.C. , Sena Emily
Published: April 2018

Background and aims

Chemotherapy-induced peripheral neuropathy (CIPN) can be a severely disabling side-effect of commonly used cancer chemotherapeutics, requiring cessation or dose reduction, impacting on survival and quality of life. Our aim was to conduct a systematic review and meta-analysis of research using animal models of CIPN to inform robust experimental design.

Methods

We systematically searched 5 online databases (PubMed, Web of Science, Citation Index, Biosis Previews and Embase (September 2012) to identify publications reporting in vivo CIPN modelling. Due to the number of publications and high accrual rate of new studies, we ran an updated search November 2015, using machine-learning and text mining to identify relevant studies.

All data were abstracted by two independent reviewers. For each comparison we calculated a standardised mean difference effect size then combined effects in a random effects meta- analysis. The impact of study design factors and reporting of measures to reduce the risk of bias was assessed. We ran power analysis for the most commonly reported behavioural tests.

Results

341 publications were included. The majority (84%) of studies reported using male animals to model CIPN; the most commonly reported strain was Sprague Dawley rat. In modelling experiments, Vincristine was associated with the greatest increase in pain-related behaviour (−3.22 SD [−3.88; −2.56], n=152, p=0). The most commonly reported outcome measure was evoked limb withdrawal to mechanical monofilaments. Pain-related complex behaviours were rarely reported. The number of animals required to obtain 80% power with a significance level of 0.05 varied substantially across behavioural tests. Overall, studies were at moderate risk of bias, with modest reporting of measures to reduce the risk of bias.

Conclusions

Here we provide a comprehensive summary of the field of animal models of CIPN and inform robust experimental design by highlighting measures to increase the internal and external validity of studies using animal models of CIPN. Power calculations and other factors, such as clinical relevance, should inform the choice of outcome measure in study design.
Distinct sequence patterns in the active postmortem transcriptome
Authors: Noble Peter A , Pozhitkov Alexander E.
Published: April 2018

Our previous study found more than 500 transcripts significantly increased in abundance in the zebrafish and mouse several hours to days postmortem relative to live controls. The current literature suggests that most mRNAs are post-transcriptionally regulated in stressful conditions, we rationalized that the postmortem transcripts must contain sequence features (3 to 9 mers) that are unique from those in the rest of the transcriptome – specifically, binding sites for proteins and/or non-coding RNAs involved in regulation. Our new study identified 5117 and 2245 over-represented sequence features in the mouse and zebrafish, respectively. Some of these features were disproportionately distributed along the transcripts with high densities in the 3-UTR region of the zebrafish (0.3 mers/nt) and the ORFs of the mouse (0.6 mers/nt). Yet, the highest density (2.3 mers/nt) occurred in the ORFs of 11 mouse transcripts that lacked UTRs. Our results suggest that these transcripts might serve as ‘molecular sponges’ that sequester RNA binding proteins and/or microRNAs, increasing the stability and gene expression of other transcripts. In addition, some features were identified as binding sites forRbfoxandHudproteins that are also involved in increasing transcript stability and gene expression. Hence, our results are consistent with the hypothesis that transcripts involved in responding to extreme stress have sequence features that make them different from the rest of the transcriptome, which presumably has implications for post-transcriptional regulation in disease, starvation, and cancer.

ABBREVIATIONS

UTR

untranslated regions

ORFs

open reading frames

OP

overabundant transcript pool

CP

control transcript pool

FP

false positive

RBP

RNA binding proteins

ncRNA

non-coding RNA

miRNA

microRNA
Estimating the frequency of multiplets in single-cell RNA sequencing from cell-mixing experiments
Authors: Bloom Jesse D.
Published: April 2018

In single-cell RNA-sequencing, it is important to know the frequency at which the sequenced transcriptomes actually derive from multiple cells. A common method to estimate this multiplet frequency is to mix two different types of cells (e.g., human and mouse), and then determine how often the transcriptomes contain transcripts from both cell types. When the two cell types are mixed in equal proportion, the calculation of the multiplet frequency from the frequency of mixed transcriptomes is straightforward. But surprisingly, there are no published descriptions of how to calculate the multiplet frequency in the general case when the cell types are mixed unequally. Here I derive equations to analytically calculate the multiplet frequency from the numbers of observed pure and mixed transcriptomes when two cell types are mixed in arbitrary proportions, under the assumption that the loading of cells into droplets or wells is Poisson.
Exceptional response to everolimus in a novel tuberous sclerosis complex-2 mutation–associated metastatic renal-cell carcinoma
Authors: Alsidawi Samer , Kasi Pashtoon Murtaza
Published: April 2018

Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR) pathway, is currently approved for treatment of advanced renal-cell carcinoma (RCC) after failure of initial treatment with the tyrosine kinase inhibitors. Patients with tuberous sclerosis complex (TSC) syndrome can also develop RCC primarily mediated through mTOR signaling. However, the efficacy and duration of response of mTOR inhibition in patients with TSC-associated RCC is not well known. Herein, we describe a case of a patient withTSC2-associated metastatic RCC with mutationsH1620RandY1650Cwho has had an exceptional response to everolimus in the frontline setting and continues to derive benefit from mTOR inhibition 2 yr into therapy. Furthermore, the alterationH1620Rin exon 37 resulting in a missense mutation is likely deleterious given our findings and previous analyses of theTSC2gene. Further studies of somatic mutations in extended responders to mTOR inhibitors will help personalize therapy for these patients. It also emphasizes the value of targeted therapies based on genomic analyses.
Clinically actionable mutation profiles in patients with cancer identified by whole-genome sequencing
Authors: Schuh Anna , Dreau Helene , Knight Samantha J.L. , Ridout Kate , Mizani Tuba , Vavoulis Dimitris , Colling Richard , Antoniou Pavlos , Kvikstad Erika M. , Pentony Melissa M. , Hamblin Angela , Protheroe Andrew , Parton Marina , Shah Ketan A. , Orosz Zsolt , Athanasou Nick , Hassan Bass , Flanagan Adrienne M. , Ahmed Ahmed , Winter Stuart , Harris Adrian , Tomlinson Ian , Popitsch Niko , Church David , Taylor Jenny C.
Published: April 2018

Next-generation sequencing (NGS) efforts have established catalogs of mutations relevant to cancer development. However, the clinical utility of this information remains largely unexplored. Here, we present the results of the first eight patients recruited into a clinical whole-genome sequencing (WGS) program in the United Kingdom. We performed PCR-free WGS of fresh frozen tumors and germline DNA at 75× and 30×, respectively, using the HiSeq2500 HTv4. Subtracted tumor VCFs and paired germlines were subjected to comprehensive analysis of coding and noncoding regions, integration of germline with somatically acquired variants, and global mutation signatures and pathway analyses. Results were classified into tiers and presented to a multidisciplinary tumor board. WGS results helped to clarify an uncertain histopathological diagnosis in one case, led to informed or supported prognosis in two cases, leading to de-escalation of therapy in one, and indicated potential treatments in all eight. Overall 26 different tier 1 potentially clinically actionable findings were identified using WGS compared with six SNVs/indels using routine targeted NGS. These initial results demonstrate the potential of WGS to inform future diagnosis, prognosis, and treatment choice in cancer and justify the systematic evaluation of the clinical utility of WGS in larger cohorts of patients with cancer.
Genomic profiling of dedifferentiated liposarcoma compared to matched well-differentiated liposarcoma reveals higher genomic complexity and a common origin
Authors: Beird Hannah C. , Wu Chia-Chin , Ingram Davis R. , Wang Wei-Lien , Alimohamed Asrar , Gumbs Curtis , Little Latasha , Song Xingzhi , Feig Barry W. , Roland Christina L. , Zhang Jianhua , Benjamin Robert S. , Hwu Patrick , Lazar Alexander J. , Futreal P. Andrew , Somaiah Neeta
Published: April 2018

Well-differentiated (WD) liposarcoma is a low-grade mesenchymal tumor with features of mature adipocytes and high propensity for local recurrence. Often, WD patients present with or later progress to a higher-grade nonlipogenic form known as dedifferentiated (DD) liposarcoma. These DD tumors behave more aggressively and can metastasize. Both WD and DD liposarcomas harbor neochromosomes formed from amplifications and rearrangements of Chr 12q that encode oncogenes (MDM2, CDK4, and YEATS2) and adipocytic differentiation factors (HMGA2 and CPM). However, genomic changes associated with progression from WD to DD have not been well-defined. Therefore, we selected patients with matched WD and DD tumors for extensive genomic profiling in order to understand their clonal relationships and to delineate any defining alterations for each entity. Exome and transcriptomic sequencing was performed for 17 patients with both WD and DD diagnoses. Somatic point and copy-number alterations were integrated with transcriptional analyses to determine subtype-associated genomic features and pathways. The results were, on average, that only 8.3% of somatic mutations in WD liposarcoma were shared with their cognate DD component. DD tumors had higher numbers of somatic copy-number losses, amplifications involving Chr 12q, and fusion transcripts than WD tumors. HMGA2 and CPM rearrangements occur more frequently in DD components. The shared somatic mutations indicate a clonal origin for matched WD and DD tumors and show early divergence with ongoing genomic instability due to continual generation and selection of neochromosomes. Stochastic generation and subsequent expression of fusion transcripts from the neochromosome that involve adipogenesis genes such as HMGA2 and CPM may influence the differentiation state of the subsequent tumor.