bluuebunny/crossref_metadata_2025 huggingface dataset:
A global overview of pleiotropy and genetic architecture in complex traits
Authors: Watanabe Kyoko , Stringer Sven , Frei Oleksandr , Mirkov Maša Umićević , Polderman Tinca J.C. , van der Sluis Sophie , Andreassen Ole A. , Neale Benjamin M. , Posthuma Danielle
Published: December 2018

After a decade of genome-wide association studies (GWASs), fundamental questions in human genetics are still unanswered, such as the extent of pleiotropy across the genome, the nature of trait-associated genetic variants and the disparate genetic architecture across human traits. The current availability of hundreds of GWAS results provide the unique opportunity to gain insight into these questions. In this study, we harmonized and systematically analysed 4,155 publicly available GWASs. For a subset of well-powered GWAS on 558 unique traits, we provide an extensive overview of pleiotropy and genetic architecture. We show that trait associated loci cover more than half of the genome, and 90% of those loci are associated with multiple trait domains. We further show that potential causal genetic variants are enriched in coding and flanking regions, as well as in regulatory elements, and how trait-polygenicity is related to an estimate of the required sample size to detect 90% of causal genetic variants. Our results provide novel insights into how genetic variation contributes to trait variation. All GWAS results can be queried and visualized at the GWAS ATLAS resource (http://atlas.ctglab.nl).
Functional evaluation of transposable elements as transcriptional enhancers in mouse embryonic and trophoblast stem cells
Authors: Todd Christopher D. , Deniz Özgen , Branco Miguel R.
Published: December 2018

The recurrent invasion and expansion of transposable elements (TEs) throughout evolution brought with it a vast array of coding and non-coding sequences that can serve as substrates for natural selection. Namely, TEs are thought to have contributed to the establishment of gene regulatory networks via their cis-acting elements. Both the embryonic and extraembryonic lineages of the early mouse embryo are thought to have benefited from the co-option of TEs as distal enhancer elements. However, there is little to no evidence that these particular TEs play significant roles in the regulation of gene expression. Here we tested for roles of TEs as enhancers in mouse embryonic and trophoblast stem cells by combining bioinformatic analyses with genetic and epigenetic editing experiments. Epigenomic and transcriptomic data from wildtype cells suggested that a large number of TEs played a role in the establishment of highly tissue-specific gene expression programmes. Through genetic editing of individual TEs we confirmed a subset of these regulatory relationships. However, a wider survey via CRISPR interference of RLTR13D6 elements in embryonic stem cells revealed that only a minority play significant roles in gene regulation. Our results suggest that a small proportion of TEs contribute to the mouse pluripotency regulatory network, and highlight the importance of functional experiments when evaluating the role of TEs in gene regulation.
Female genetic contributions to sperm competition in Drosophila melanogaster
Authors: Chen Dawn S. , Delbare Sofie Y.N. , White Simone L. , Sitnik Jessica L. , Chatterjee Martik , DoBell Elizabeth L. , Weiss Orli D. , Clark Andrew G. , Wolfner Mariana F.
Published: December 2018

In many species, sperm can remain viable in the reproductive tract of a female well beyond the typical interval to remating. This creates an opportunity for sperm from different males to compete for oocyte fertilization inside the female’s reproductive tract. In Drosophila melanogaster, sperm morphology and seminal fluid content affect male success in sperm competition. On the other hand, although genome-wide association studies (GWAS) have demonstrated that female genotype plays a role in sperm competition outcome as well, the biochemical, sensory and physiological processes by which females detect and selectively use sperm from different males remain elusive. Here, we functionally tested 27 candidate genes implicated via a GWAS for their contribution to the female’s role in sperm competition, measured as changes in the relative success of the first male to mate (P1). Of these 27 candidates, we identified eight genes that affect P1 when knocked down in females, and also showed that six of them do so when knocked down in the female nervous system. Two genes in particular, Rim and caup, lowered P1 when knocked down in sensory pickpocket (ppk)+ neurons and octopaminergic Tdc2+ neurons, respectively. These results establish a functional role for the female’s nervous system in the process of sperm competition and expand our understanding of the genetic, neuronal and mechanistic basis of female responses to multiple matings. We propose that through their nervous system, females actively assess male compatibility based on courtship or ejaculates and modulate sperm competition outcome accordingly.
Depopulation of α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model
Authors: Wegrzynowicz Michal , Bar-On Dana , Calo’ Laura , Anichtchik Oleg , Iovino Mariangela , Xia Jing , Ryazanov Sergey , Leonov Andrei , Giese Armin , Dalley Jeffrey W. , Griesinger Christian , Ashery Uri , Spillantini Maria Grazia
Published: December 2018

Parkinson’s Disease (PD) is characterized by the presence of α-synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between α-synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) expressing human, aggregation-prone truncated 1-120 α-synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of α-synuclein in dopaminergic neurons of the substantia nigra pars compacta and their striatal terminals. This is associated with a progressive reduction of striatal dopamine release, reduced striatal innervation and significant nigral dopaminergic nerve cell death starting from 6 and 12 months of age, respectively. Overt impairment in motor behavior was found in MI2 mice at 20 months of age, when 50% of dopaminergic neurons are lost. These changes were associated with an increase in the number and density of 20-500nm α-synuclein species as shown by dSTORM. Treatment with the oligomer modulator anle138b, from 9-12 months of age, restored striatal dopamine release and prevented dopaminergic cell death. These effects were associated with a reduction of the inner density of α-synuclein aggregates and an increase in dispersed small α-synuclein species as revealed by dSTORM. The MI2 mouse model recapitulates the progressive dopaminergic deficit observed in PD, showing that early synaptic dysfunction precedes dopaminergic axonal loss and neuronal death that become associated with a motor deficit upon reaching a certain threshold. Our data also provide new mechanistic insight for the effect of anle138b’s function in vivo supporting that targeting α-synuclein aggregation is a promising therapeutic approach for PD.
Text-mining clinically relevant cancer biomarkers for curation into the CIViC database
Authors: Lever Jake , Jones Martin R , Danos Arpad M , Krysiak Kilannin , Bonakdar Melika , Grewal Jasleen , Culibrk Luka , Griffith Obi L , Griffith Malachi , Jones Steven JM
Published: December 2018

Precision oncology involves analysis of individual cancer samples to understand the genes and pathways involved in the development and progression of a cancer. To improve patient care, knowledge of diagnostic, prognostic, predisposing and drug response markers is essential. Several knowledgebases have been created by different groups to collate evidence for these associations. These include the open-access Clinical Interpretation of Variants in Cancer (CIViC) knowledgebase. These databases rely on time-consuming manual curation from skilled experts who read and interpret the relevant biomedical literature. To aid in this curation and provide the greatest coverage for these databases, particularly CIViC, we propose the use of text mining approaches to extract these clinically relevant biomarkers from all available published literature. To this end, a group of cancer genomics experts annotated biomarkers and their clinical associations discussed in 800 sentences and achieved good inter-annotator agreement. We then used a supervised learning approach to construct the CIViCmine knowledgebase (http://bionlp.bcgsc.ca/civicmine/) extracting 128,857 relevant sentences from PubMed abstracts and Pubmed Central Open Access full text papers. CIViCmine contains over 90,992 biomarkers associated with 7,866 genes, 402 drugs and 557 cancer types, representing 29,153 abstracts and 40,551 full-text publications. Through integration with CIVIC, we provide a prioritised list of curatable biomarkers as well as a resource that is valuable to other knowledgebases and precision cancer analysts in general.
Similarities and differences between native HIV-1 envelope glycoprotein trimers and stabilized soluble trimer mimetics
Authors: la Peña Alba Torrents de , Rantalainen Kimmo , Cottrell Christopher A. , Allen Joel D. , van Gils Marit J. , Torres Jonathan L. , Crispin Max , Sanders Rogier W. , Ward Andrew B.
Published: December 2018

The HIV-1 envelope glycoprotein (Env) trimer is located on the surface of the virus and is the target of broadly neutralizing antibodies (bNAbs). Recombinant native-like soluble Env trimer mimetics, such as SOSIP trimers, have taken a central role in HIV-1 vaccine research aimed at inducing bNAbs. We therefore performed a direct and thorough comparison of a full-length native Env trimer containing the transmembrane domain and the cytoplasmic tail, with the sequence matched soluble SOSIP trimer, both based on an early Env sequence (AMC011) from an HIV+ individual that developed bNAbs. The structures of the full-length AMC011 trimer bound to either bNAb PGT145 or PGT151 were very similar to the structures of SOSIP trimers. Antigenically, the full-length and SOSIP trimers were comparable, but in contrast to the full-length trimer, the SOSIP trimer did not bind at all to non-neutralizing antibodies, most likely as a consequence of the intrinsic stabilization of the SOSIP trimer. Furthermore, the glycan composition of full-length and SOSIP trimers was similar overall, but the SOSIP trimer possessed slightly less complex and less extensively processed glycans, which may relate to the intrinsic stabilization as well as the absence of the membrane tether. These data provide insights into how to best use and improve membrane-associated full-length and soluble SOSIP HIV-1 Env trimers as immunogens.
Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study
Authors: Zhu Yihui , Mordaunt Charles E. , Yasui Dag H. , Marathe Ria , Coulson Rochelle L. , Dunaway Keith W. , Walker Cheryl K. , Ozonoff Sally , Hertz-Picciotto Irva , Schmidt Rebecca J. , LaSalle Janine M.
Published: December 2018

DNA methylation acts at the interface of genetic and environmental factors relevant for autism spectrum disorder (ASD). Placenta, normally discarded at birth, is a potentially rich source of DNA methylation patterns predictive of ASD in the child. Here, we performed whole methylome analyses of placentas from a prospective study of high-risk pregnancies. 400 differentially methylated regions (DMRs) discriminated placentas stored from children later diagnosed with ASD compared to typical controls. These ASD DMRs were significantly enriched at promoters, mapped to 596 genes functionally enriched in neuronal development, and overlapped genetic ASD risk. ASD DMRs at CYP2E1 and IRS2 reached genome-wide significance, replicated by pyrosequencing, and correlated with expression. Methylation at CYP2E1 associated with both ASD diagnosis and cis genotype, while methylation at IRS2 was unaffected by cis genotype but modified by preconceptional maternal prenatal vitamin use. This study therefore identified two potentially useful early epigenetic markers for ASD in placenta.
Neuromusculoskeletal simulation reveals abnormal rectus femoris-gluteus medius reflex coupling in post-stroke gait
Authors: Akbas Tunc , Neptune Richard R. , Sulzer James
Published: December 2018

Post-stroke gait is often accompanied by muscle impairments that result in adaptations such as hip circumduction to compensate for lack of knee flexion. Our previous work robotically enhanced knee flexion in individuals post-stroke with Stiff-Knee Gait (SKG), however, this resulted in greater circumduction, suggesting the existence of abnormal coordination in SKG. The purpose of this work is to investigate two possible mechanisms of the abnormal coordination: 1) an involuntary coupling between stretched quadriceps and abductors, and 2) a coupling between volitionally activated knee flexors and abductors. We used previously collected kinematic, kinetic and EMG measures from nine participants with chronic stroke and five healthy controls during walking with and without the applied knee flexion torque perturbations in the pre-swing phase of gait in the neuromusculoskeletal simulation. The measured muscle activity was supplemented by simulated muscle activations to estimate the muscle states of the quadriceps, hamstrings and hip abductors. We used linear mixed models to investigate two hypotheses: H1) association between quadriceps and abductor activation during an involuntary period (reflex latency) following the perturbation and H2) association between hamstrings and abductor activation after the perturbation was removed. We observed significantly higher rectus femoris (RF) activation in stroke participants compared to healthy controls within the reflex latency period following the perturbation based on both measured (H1, p < 0.001) and simulated (H1, p = 0.022) activity. Simulated RF and gluteus medius (GMed) activations were correlated only in those with SKG, which was significantly higher compared to healthy controls (H1, p = 0.030). There was no evidence of voluntary synergistic coupling between any combination of hamstrings and hip abductors (H2, p > 0.05) when the perturbation was removed. The RF-GMed coupling suggests an underlying abnormal reflex coordination pattern in post-stroke SKG. These results challenge earlier assumptions that hip circumduction in stroke is simply a kinematic adaptation due to reduced toe clearance. Instead, abnormal coordination may underlie circumduction, illustrating the deleterious role of abnormal coordination in post-stroke gait.
Fast and accurate differential transcript usage by testing equivalence class counts
Authors: Cmero Marek , Davidson Nadia M , Oshlack Alicia
Published: December 2018

RNA sequencing has enabled high-throughput and fine-grained quantitative analyses of the transcriptome. While differential gene expression is the most widely used application of this technology, RNA-seq data also has the resolution to infer differential transcript usage (DTU), which can elucidate the role of different transcript isoforms between experimental conditions, cell types or tissues. DTU has typically been inferred from exon-count data, which has issues with assigning reads unambiguously to counting bins, and requires alignment of reads to the genome. Recently, approaches have emerged that use transcript quantifications estimates directly for DTU. Transcript counts can be inferred from ‘pseudo’ or lightweight aligners, which are significantly faster than traditional genome alignment. However, recent evaluations show lower sensitivity in DTU analysis. Transcript abundances are estimated from equivalence classes (ECs), which determine the transcripts that any given read is compatible with. Here we propose performing DTU testing directly on equivalence class read counts. We evaluate this approach on simulated human and drosophila data, as well as on a real dataset through subset testing. We find that ECs counts have similar sensitivity and false discovery rates as exon-level counts but can be generated in a fraction of the time through the use of pseudo-aligners. We posit that equivalent class counts is a natural unit on which to perform many types of analysis.
A simple new approach to variable selection in regression, with application to genetic fine-mapping
Authors: Wang Gao , Sarkar Abhishek , Carbonetto Peter , Stephens Matthew
Published: December 2018

We introduce a simple new approach to variable selection in linear regression, with a particular focus onquantifying uncertainty in which variables should be selected. The approach is based on a new model — the “Sum of Single Effects” (SuSiE) model — which comes from writing the sparse vector of regression coefficients as a sum of “single-effect” vectors, each with one non-zero element. We also introduce a corresponding new fitting procedure — Iterative Bayesian Stepwise Selection (IBSS) — which is a Bayesian analogue of stepwise selection methods. IBSS shares the computational simplicity and speed of traditional stepwise methods, but instead of selecting a single variable at each step, IBSS computes adistributionon variables that captures uncertainty in which variable to select. We provide a formal justification of this intuitive algorithm by showing that it optimizes a variational approximation to the posterior distribution under theSuSiEmodel. Further, this approximate posterior distribution naturally yields convenient novel summaries of uncertainty in variable selection, providing a Credible Set of variables for each selection. Our methods are particularly well-suited to settings where variables are highly correlated and detectable effects are sparse, both of which are characteristics of genetic fine-mapping applications. We demonstrate through numerical experiments that our methods outper-form existing methods for this task, and illustrate their application to fine-mapping genetic variants influencing alternative splicing in human cell-lines. We also discuss the potential and challenges for applying these methods to generic variable selection problems.
M1 disruption delays motor processes but not deliberation about action choices
Authors: Derosiere Gerard , Thura David , Cisek Paul , Duque Julie
Published: December 2018

Decisions about actions typically involve a period of deliberation that ends with the commitment to a choice and the motor processes overtly expressing that choice. Previous studies have shown that neural activity in sensorimotor areas, including the primary motor cortex (M1), correlates with deliberation features during action selection. Yet, the causal contribution of these areas to the decision process remains unclear. Here, we investigated whether M1 determines choice commitment, or whether it simply reflects decision signals coming from upstream structures and instead mainly contributes to the motor processes that follow commitment. To do so, we tested the impact of a disruption of M1 activity, induced by continuous theta burst stimulation (cTBS), on the behavior of human subjects in (1) a simple reaction time (SRT) task allowing us to estimate the duration of the motor processes and (2) a modified version of the tokens task (Cisek et al., 2009), which allowed us to estimate subjects’ time of commitment as well as accuracy criterion. The efficiency of cTBS was attested by a reduction in motor evoked potential amplitudes following M1 disruption, as compared to those following a sham stimulation. Furthermore, M1 cTBS lengthened SRTs, indicating that motor processes were perturbed by the intervention. Importantly, all of the behavioral results in the tokens task were similar following M1 disruption and sham stimulation, suggesting that the contribution of M1 to the deliberation process is potentially negligible. Taken together, these findings favor the view that M1 contribution is downstream of the decision process.

New and noteworthy

Decisions between actions are ubiquitous in the animal realm. Deliberation during action choices entails changes in the activity of the sensorimotor areas controlling those actions, but the causal role of these areas is still often debated. Using continuous theta burst stimulation, we show that disrupting the primary motor cortex (M1) delays the motor processes that follow instructed commitment but does not alter volitional deliberation, suggesting that M1 contribution may be downstream of the decision process.
Dynamic changes in the brain protein interaction network correlates with progression of Aβ42 pathology in Drosophila
Authors: Scholes Harry M. , Cryar Adam , Kerr Fiona , Sutherland David , Gethings Lee A. , Vissers Johannes P. C. , Lees Jonathan G. , Orengo Christine A. , Partridge Linda , Thalassinos Konstantinos
Published: December 2018

Alzheimer’s disease (AD), the most prevalent form of dementia, is a progressive and devastating neurodegenerative condition for which there are no effective treatments. Understanding the molecular pathology of AD during disease progression may identify new ways to reduce neuronal damage. Here, we present a longitudinal study tracking dynamic proteomic alterations in the brains of an inducible Drosophila melanogaster model of AD expressing the Arctic mutant Aβ42 gene. We identified 3093 proteins from flies that were induced to express Aβ42 and age-matched healthy controls using label-free quantitative ion-mobility data independent analysis mass spectrometry. Of these, 228 proteins were significantly altered by Aβ42 accumulation and were enriched for AD-associated processes. Network analyses further revealed that these proteins have distinct hub and bottleneck properties in the brain protein interaction network, suggesting that several may have significant effects on brain function. Our unbiased analysis provides useful insights into the key processes governing the progression of amyloid toxicity and forms a basis for further functional analyses in model organisms and translation to mammalian systems.
Injection of antibodies against immunodominant epitopes tunes germinal centres to generate broadly neutralizing antibodies
Authors: Meyer-Hermann Michael
Published: December 2018

The development of broadly neutralizing antibodies is critical for the control of many life-threatening viral infections like HIV, influenza, or hepatitis. Elite neutralizers are generated by natural germinal centre (GC) reactions in a very small subset of patients. The best strategy of how to promote the generation of broadly neutralizing antibodies is not known. Here, computer simulations of GC reactions are used to predict a feedback loop based on memory B cells from previous GC reactions that promotes GCs to focus on new epitopes. The simulations suggest that the injection of antibodies against immunodominant epitopes fosters affinity maturation of antibodies specific for rare or hidden epitopes. This principle can be used for the design and testing of future therapies and vaccination protocols.
Asexual reproduction drives the reduction of transposable element load
Authors: Bast Jens , Jaron Kamil S. , Schuseil Donovan , Roze Denis , Schwander Tanja
Published: December 2018

Theory predicts that sexual reproduction can both facilitate and restrain transposable element (TE) accumulation by providing TEs with a means of spreading to all individuals in a population and facilitating TE load reduction via purifying selection. By quantifying genomic TE loads over time in experimental sexual and asexualSaccharomyces cerevisiaepopulations, we provide direct evidence that asexual reproduction drives a reduction of TE loads. We show, using simulations, that this reduction occurs via evolution of TE activity, most likely via increased excision rates. Thus, sex is a major driver of genomic TE loads and at the root of the success of TEs.
Antidepressant treatment modulates the gut microbiome and metabolome during pregnancy and lactation in rats with a depressive-like phenotype
Authors: Ramsteijn Anouschka S , Jašarević Eldin , Houwing Danielle J , Bale Tracy L , Olivier Jocelien DA
Published: December 2018

Background: Up to 10% of women use selective serotonin reuptake inhibitor (SSRI) antidepressants during and after pregnancy to manage mood disorders, with possible implications for the developing offspring. The microbiota within the gastrointestinal tract contributes to the regulation of serotonin synthesis. However, the interaction between maternal depression, SSRI use, bacterial community composition, and availability of microbiota-derived metabolites during pregnancy and lactation is not clear and may be consequential to the long-term health of mother and offspring. To determine the impact of SSRI treatment on maternal microbial community dynamics, we conducted these studies in a rat model of maternal vulnerability (MV). All MV females are on a background of genetic vulnerability, where rats exposed to early life stress (sMV) develop a depressive-like phenotype. In adulthood, sMV- and control (cMV) females were treated with either the SSRI fluoxetine (FLX) or the vehicle (Veh) throughout pregnancy and lactation. High-resolution 16S ribosomal RNA gene sequencing and targeted metabolomic analysis were used to assess the fecal microbiome and metabolite availability, respectively.
Results: The diversity, structure, and composition of the fecal bacterial community differed between pregnancy and lactation. Shifts in microbiota composition were accompanied by changes in fecal metabolite availability. FLX altered some key features of the transition from pregnancy to lactation, but only in females exposed to early life stress (sMV-Veh vs sMV-FLX). For instance, sMV-FLX females had lower fecal availability of the amino acids serine, proline, and aspartic acid than sMV-Veh females. These metabolite concentrations correlated negatively with the relative abundance of bacterial taxa Prevotella, Ruminococcus, and Oscillospira.
Conclusions: Our studies demonstrate an important relationship between antidepressant use during the perinatal period and maternal fecal metabolite availability in sMV rats, possibly through parallel changes in the maternal gut microbiome. Since maternal microbial metabolites contribute to health outcomes in offspring, insults to the maternal microbiome by SSRIs might have inter-generational consequences.
De-Novo-Designed Translational Repressors for Multi-Input Cellular Logic
Authors: Kim Jongmin , Zhou Yu , Carlson Paul , Teichmann Mario , Simmel Friedrich C. , Silver Pamela A. , Collins James J. , Lucks Julius B. , Yin Peng , Green Alexander A.
Published: December 2018

Synthetic biology aims to apply engineering principles toward the development of novel biological systems for biotechnology and medicine. Despite efforts to expand the set of high-performing parts for genetic circuits, achieving more complex circuit functions has often been limited by the idiosyncratic nature and crosstalk of commonly utilized parts. Here, we present a molecular programming strategy that implements RNA-based repression of translation usingde-novo-designed RNAs to realize high-performance orthogonal parts with mRNA detection and multi-input logic capabilities. These synthetic post-transcriptional regulators, termed toehold repressors and three-way junction (3WJ) repressors, efficiently suppress translation in response to cognate trigger RNAs with nearly arbitrary sequences using thermodynamically and kinetically favorable linear-linear RNA interactions. Automatedin silicooptimization of thermodynamic parameters yields improved toehold repressors with up to 300-fold repression, while in-cell SHAPE-Seq measurements of 3WJ repressors confirm their designed switching mechanism in living cells. Leveraging the absence of sequence constraints, we identify eight- and 15-component sets of toehold and 3WJ repressors, respectively, that provide high orthogonality. The modularity, wide dynamic range, and low crosstalk of the repressors enable their direct integration into ribocomputing devices that provide universal NAND and NOR logic capabilities and can perform multi-input RNA-based logic. We demonstrate these capabilities by implementing a four-input NAND gate and the expression NOT((A1 AND A2) OR (B1 AND B2)) inEscherichia coli. These features make toehold and 3WJ repressors important new classes of translational regulators for biotechnological applications.
ASCOT identifies key regulators of neuronal subtype-specific splicing
Authors: Ling Jonathan P , Wilks Christopher , Charles Rone , Ghosh Devlina , Jiang Lizhi , Santiago Clayton P , Pang Bo , Venkataraman Anand , Clark Brian S , Nellore Abhinav , Langmead Ben , Blackshaw Seth
Published: December 2018

Public archives of next-generation sequencing data are growing exponentially, but the difficulty of marshaling this data has led to its underutilization by scientists. Here we present ASCOT, a resource that allows researchers to summarize, visualize, and query alternative splicing patterns in public RNA-Seq data. ASCOT enables rapid identification of splice-variants across tens of thousands of bulk and single-cell RNA-Seq datasets in human and mouse. To demonstrate the utility of ASCOT, we first focused on the nervous system and identified many alternative exons used only by a single neuronal subtype. We then leveraged datasets from the ENCODE and GTEx consortiums to study the unique splicing patterns of rod photoreceptors and found that PTBP1 knockdown combined with overexpression of MSI1 and PCBP2 activates rod-specific exons in HepG2 liver cancer cells. Furthermore, we observed that MSI1 targets intronic UAG motifs proximal to the 5’ splice site and interacts synergistically with PTBP1 downregulation. Finally, we show that knockdown of MSI1 in the retina abolishes rod-specific splicing. This work demonstrates how large-scale analysis of public RNA-Seq datasets can yield key insights into cell type-specific control of RNA splicing and underscores the importance of considering both annotated and unannotated splicing events. ASCOT splicing and gene expression data tables, software, and interactive browser are available at http://ascot.cs.jhu.edu.
Prioritisation of oncology therapeutic targets using CRISPR-Cas9 screening
Authors: Behan Fiona M , Iorio Francesco , Gonçalves Emanuel , Picco Gabriele , Beaver Charlotte M , Santos Rita , Rao Yanhua , Ansari Rizwan , Harper Sarah , Jackson David Adam , McRae Rebecca , Pooley Rachel , Wilkinson Piers , Dow David , Buser-Doepner Carolyn , Stronach Euan A. , Saez-Rodriguez Julio , Yusa Kosuke , Garnett Mathew J
Published: December 2018

Functional genomics approaches can overcome current limitations that hamper oncology drug development such as lack of robust target identification and clinical efficacy. Here we performed genome-scale CRISPR-Cas9 screens in 204 human cancer cell lines from 12 cancer-types and developed a data-driven framework to prioritise cancer therapeutic candidates. We integrated gene cell fitness effects with genomic biomarkers and target tractability for drug development to systematically prioritise new oncology targets in defined tissues and genotypes. Furthermore, we took one of our most promising dependencies, Werner syndrome RecQ helicase, and verified it as a candidate target for tumours with microsatellite instability. Our analysis provides a comprehensive resource of cancer dependencies, a framework to prioritise oncology targets, and nominates specific new candidates. The principles described in this study can transform the initial stages of the drug development process contributing to a new, diverse and more effective portfolio of oncology targets.
Activation of neuromodulatory axon projections in primary visual cortex during periods of locomotion and pupil dilation
Authors: Larsen Rylan Scott , Turschak Emily , Daigle Tanya , Zeng Hongkui , Zhuang Jun , Waters Jack
Published: December 2018

Neuromodulators such as acetylcholine, noradrenaline (norepinephrine), and serotonin are released into the cortex by axons ascending from subcortical nuclei. These neuromodulators have been hypothesized to influence cortical function during behavioral periods such as arousal, locomotion, exploration, and attention. To determine when these neuromodulatory projections were active, we expressed the genetically-encoded calcium sensor GCaMP6 in neuromodulatory axons which project to the mouse primary visual cortex and performed two-photon microscopy to monitor their activity in vivo. We observed that the fluorescence of both cholinergic and noradrenergic axons increased during periods of pupil dilation, with the fluorescence of the axons rising less than one second before eye pupil dilation. We also observed increases in cholinergic and noradrenergic axon fluorescence periods of locomotion, which was accompanied by pupil dilation and nasal (forward) movement of both pupils. Locomotion was preceded by a rise in axonal fluorescence with a timing and amplitude that matched the subsequent pupil dilation, but axon fluorescence was more sustained than expected from the pupil dilation, suggesting that there is an additional physiological factor that affects cholinergic and noradrenergic axon activity in primary visual cortex during locomotion.
Romantic jealousy is positively associated with fronto-striatal, insula and limbic responses to angry faces
Authors: Zheng Xiaoxiao , Luo Lizhu , Li Jialin , Xu Lei , Zhou Feng , Gao Zhao , Becker Benjamin , Kendrick Keith M.
Published: December 2018

Romantic jealousy is a complex social emotion combining the different primary emotions of anger, fear and sadness. Previous evidence has suggested the involvement of fronto-striatal dopaminergic circuitry in clinical pathological jealousy, although little is known about overlaps with the neural representation of primary emotions involved in non-morbid jealousy. In the current study, 85 healthy subjects underwent fMRI during resting state and an emotional face recognition paradigm. A total of 150 faces (happy, angry, fearful, sad, neutral) were presented and subjects were required to identify the expression and rate its intensity. Trait romantic jealousy was assessed using the Multidimensional Jealousy Scale. Behavioral results showed that only intensity ratings of angry faces were positively associated with subjects’ jealousy scores. During processing of angry versus neutral expression faces, subjects with higher jealousy scores exhibited greater activation in the right thalamus, insula, fusiform gyrus and hippocampus, left dorsal striatum and superior parietal lobule and bilateral cerebellum and inferior frontal gyrus after controlling for trait aggression and sex. Functional connectivity between the inferior frontal gyrus and caudate was also increased. No associations with resting state functional connectivity were found. Overall, the present study demonstrates an association between romantic jealousy and increased intensity ratings of angry faces as well as in activity and functional connectivity of dorsal striatal-inferior frontal circuitry. Thus, increased emotional responsivity to social threat and enhanced activity in limbic regions and dopaminergic fronto-striatal circuitry may be features of both non-morbid and pathological jealousy.
Upper bound on the biological effects of 50/60 Hz magnetic fields mediated by radical pairs
Authors: Hore P. J.
Published: December 2018

Prolonged exposure to weak (~1 μT) extremely-low-frequency (ELF, 50/60 Hz) magnetic fields has been associated with an increased risk of childhood leukaemia. One of the few biophysical mechanisms that might account for this link involves short-lived chemical reaction intermediates known as radical pairs. In this report, we use spin dynamics simulations to derive an upper bound of 10 parts per million on the effect of a 1 μT ELF magnetic field on the yield of a radical pair reaction. By comparing this figure with the corresponding effects of changes in the strength of the Earth’s magnetic field, we conclude that if exposure to such weak 50/60 Hz magnetic fields has any effect on human biology, and results from a radical pair mechanism, then the risk should be no greater than travelling a few kilometres towards or away from the geomagnetic north or south pole.
Chilling, irradiation and transport of male Glossina palpalis gambiensis pupae: effect on the emergence, flight ability and survival.
Authors: Diallo Souleymane , Seck Momar Talla , Rayaissé Jean Baptiste , Fall Assane Gueye , Bassene Mireille Djimangali , Sall Baba , Sanon Antoine , Vreysen Marc JB , Takac Peter , Parker Andrew Gordon , Gimonneau Geoffrey , Bouyer Jérémy
Published: December 2018

Background
The sterile insect technique (SIT) requires mass-rearing of the target species, irradiation to induce sexual sterility and transportation from the mass-rearing facility to the target site. Those treatments require several steps that may affect the biological quality of sterile males. This study has been carried out to evaluate the relative impact of the chilling, irradiation and transport on emergence rate, flight ability and survival of sterile male tsetse flies Glossina palpalis gambiensis.
Results
Chilling, irradiation and transport all affected the quality control parameters studied. The emergence rate was significantly reduced by long chilling periods and transport, i.e. from 92% at the source insectary to 78% upon arrival in Dakar. Flight ability was affected by all three parameters with 31% operational flies lossed between the source and arrival insectaries. Only survival under stress was not affected by any of the treatments.
Conclusion
The chilling period and transport were the main treatments which impacted significantly the quality of sterile male pupae. Therefore, the delivery of sterile males was divided over two shipments per week in order to reduce the chilling time and improve the quality of the sterile males. Quality of the male pupae may further be improved by reducing the transport time and vibration during transport.
Keys words: Tsetse flies, mass-rearing conditions, sterile insect technique, quality
Off-target effects of Cre recombinase reveal limits of adoptive T cell transfers and persistent proliferation of effector CD8 T-cells
Authors: Borkner Lisa , Drabig Anja , Zheng Xiaoyan , Drylewicz Julia , Marandu Thomas , Baliu-Piqué Mariona , van Duikeren Suzanne , Arens Ramon , Tesselaar Kiki , Borghans José AM , Čičin-Šain Luka
Published: December 2018

Effector-memory T-cells (TEM) are assumed to be short-lived cells that poorly proliferate upon antigenic restimulation, thus depending on central-memory T-cells (TCM) to replenish their numbers during homeostasis, largely depending on adoptive transfer evidence. Here we analyzed T cells in their natural environment and observed robust long-term in vivo cycling within the TEM subset that was stronger than the one in the TCM subset. We compared the non-persistent vaccinia virus and the persisting murine Cytomegalovirus (MCMV), which induces inflationary TEM responses that remain high during viral latency. We analyzed Ki67 expression during acute, resolved and latent infection and found Ki67hiBcl2lo TEM in acutely or latently infected mice, arguing for antigen-driven TEM proliferation. In vivo labeling with deuterium showed that TEM acquired deuterium more rapidly than TCM, and were rapidly lost during chase. Similarly, antibody-mediated depletion of primed CD8 T cells in latenly infected mice revealed that TEM replenished more rapidly than TCM, suggesting that TEM cycle faster than TCM. Finally, we utilized the ability of Tamoxifen-induced Cre-ERT2 recombinase to induce chromosomal translocations when large amounts of Tamoxifen are administered for an extended time, which resulted in a selective depletion of proliferating Ki67hi cells that hardly affected the TCM subset, but drove a selective loss of Ki67hiBcl2lo effector T-cells, and an increase in the death of TEM in the spleen, arguing that TEM preferentially proliferate in the spleen. Since our results contradicted previous evidence from adoptive transfer experiments, we tested T cell homing to the spleen upon adoptive transfer. TEM homing was substantially poorer than the one of TCM, likely explaining the previously reported expansions of TCM, but not TEM, upon transfer into latently infected mice. In conclusion, our data suggest that memory inflation is largely maintained by splenic proliferation of antigen-specific TEM, rather than by continued expansion and differentiation of TCM.
Source reconstruction of broadband EEG/MEG data using the frequency-adaptive broadband (FAB) beamformer
Authors: Treder Matthias , Nolte Guido
Published: December 2018

A beamformer enhances the signal from a voxel of interest by minimising interference from all other locations represented in the sensor covariance matrix. However, the presence of narrowband oscillations in EEG/MEG implies that the spatial structure of the covariance matrix, and hence also the optimal beamformer, depends on the frequency.
The frequency-adaptive broadband (FAB) beamformer introduced here exploits this fact in the Fourier domain by partitioning the covariance matrix into cross-spectra corresponding to different frequencies. For each frequency bin, an individual spatial filter is constructed. This assures optimal noise suppression across the frequency spectrum. After applying the spatial filters in the frequency domain, the broadband source signal is recovered using the inverse Fourier transform.
MEG simulations using artificial data and real resting-state measurements were used to compare the FAB beamformer to the LCMV beamformer and MNE. The FAB beamformer significantly outperforms both methods in terms of the quality of the reconstructed time series.
To our knowledge, the FAB beamformer is the first beamforming approach tailored for the analysis of broadband neuroimaging data. Due to its frequency-adaptive noise suppression, the reconstructed source time series is suited for further time-frequency or connectivity analysis in source space.
Intentions to use patient-initiated partner notification and acceptability of provider-initiated partner notification for Sexually Transmitted Infections – A cross-sectional survey among minibus taxi drivers in Gauteng Province, South Africa
Authors: mokgatle mathildah mpata , Madiba Sphiwe
Published: December 2018

Background

In South Africa, utilization of patient-initiated partner-notification (PN) using referral-slip in the management of sexually transmitted infections (STIs) is limited and only a limited number of sexual partners are ever notified. The study assessed the use of patient-initiated PN method using notification and referral slips and measured the level of acceptability of provider-initiated PN using short-message-service (SMS) to personal mobile phones of sexual partners.

Methods

A quantitative survey using anonymous structured self-administered and researcher assisted questionnaires was conducted among minibus taxi drivers in the nine major taxi ranks in Gauteng province, South Africa.

Results

The sample consisted of 722 minibus taxi drivers with a mean age of 37.2 years old, 284 (59.5%) had multiple sexual partners, 368 (52.2%) did not use a condom during last sexual act, 286 (42.8%) reported inconsistent use of condoms, and 459 (65%) tested for HIV in the past 12 months. Majority (n=709, 98.2%) understood the importance of PN once diagnosed with STI, but would prefer delivering PN referral slip (n=670, 93.2%) over telling a partner face to face if they themselves were diagnosed with STI. Acceptability of provider-initiated PN using SMS was 452 (62.7%) and associated with history of HIV testing in the past year (OR=1.72, p=0.002, CI: 1.21-2.45). The perceived use of PN referral-slip from sexual partner to seek treatment was 91.8% (n=659). About a third (n=234, 32.5%) were not in favor of provider-initiated PN by SMS and preferred telling partners face to face.

Conclusion

There were contrasting findings on the acceptability and utilization of existing patient-initiated PN and the proposed PN using SMS from health providers. The preference of delivering PN referral slip to sexual partner over face-to-face PN renders communicating about STIs the responsibility of health providers. Therefore, they have an opportunity to provide patients with options to choose a PN method that is best suited to their relationships and circumstances and modify PN messages to encourage partners to use the different PN to prevent STIs.
Asymbiotic nitrogen fixation is greater in soils under long-term no-till versus conventional tillage
Authors: Franzen David W. , Inglett Patrick W. , Gasch Caley K.
Published: December 2018

A series of N-rate experiments was previously conducted in spring wheat, corn and sunflower in North Dakota indicated that less N was required when fields were in 6-years or more continuous no-till compared to conventional till. The objective of this study was to determine whether part of the reason for the decreased requirement for N was the greater activity of asymbiotic N-fixing organisms. Twelve paired-samplings were conducted in 2018. A surface 0-5cm deep sample was obtained in a long-term no-till field directly across the fence/road from a similar soil in conventional till. Samples were incubated in an acetylene-reduction procedure to estimate N fixation rate. Ten of twelve paired samplings had greater asymbiotic N fixation compared to the conventional till counterpart. This indicates that long-term no-till soils support greater N production from soil microorganisms than conventional till soils, which would result in lower input costs to no-till farmers.
Family-specific genotype arrays increase the accuracy of pedigree based imputation at very low marker densities
Authors: Whalen Andrew , Hickey John M , Gorjanc Gregor
Published: December 2018

In this paper we evaluate the performance of using a family-specific low-density genotype arrays to increase the accuracy of pedigree based imputation. Genotype imputation is a widely used tool that decreases the costs of genotyping a population by genotyping the majority of individuals using a low-density array and using statistical regularities between the low-density and high-density individuals to fill in the missing genotypes. Previous work on population based imputation has found that it is possible to increase the accuracy of imputation by maximizing the number of informative markers on an array. In the context of pedigree based imputation, where the informativeness of a marker depends only on the genotypes of an individual's parents, it may be beneficial to select the markers on each low-density array on a family-by-family basis. In this paper we examined four family-specific low-density marker selection strategies, and evaluated their performance in the context of a real pig breeding dataset. We found that family-specific or sire-specific arrays could increase imputation accuracy by 0.11 at 1 marker per chromosome, by 0.027 at 25 markers per chromosome and by 0.007 at 100 markers per chromosome. These results suggest that there may be a room to use family-specific genotyping for very-low-density arrays particularly if a given sire or sire-dam pairing have a large number of offspring.