bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single Cortical Neurons as Deep Artificial Neural Networks
Authors: Beniaguev David , Segev Idan , London Michael 
Published: April 2019

AbstractWe introduce a novel approach to study neurons as sophisticated I/O information processing units by utilizing recent advances in the field of machine learning. We trained deep neural networks (DNNs) to mimic the I/O behavior of a detailed nonlinear model of a layer 5 cortical pyramidal cell, receiving rich spatio-temporal patterns of input synapse activations. A Temporally Convolutional DNN (TCN) with seven layers was required to accurately, and very efficiently, capture the I/O of this neuron at the millisecond resolution. This complexity primarily arises from local NMDA-based nonlinear dendritic conductances. The weight matrices of the DNN provide new insights into the I/O function of cortical pyramidal neurons, and the approach presented can provide a systematic characterization of the functional complexity of different neuron types. Our results demonstrate that cortical neurons can be conceptualized as multi-layered “deep” processing units, implying that the cortical networks they form have a non-classical architecture and are potentially more computationally powerful than previously assumed.
Microeconomics of metabolism: Overflow metabolism as Giffen behaviour
Authors: Yamagishi Jumpei F. , Hatakeyama Tetsuhiro S. 
Published: April 2019

AbstractBiological systems such as intracellular metabolism are rationally regulated to maximize the cellular growth rate through evolution (1–4), whereas microeconomics investigates the behaviour of consumers assumed to rationally maximize their utility (5, 6). Despite this analogy as optimization problems, the link between biology and economics has not been fully established (7, 8). Here, we developed an exact mapping between the regulation of metabolism and the theory of consumer choice, thereby revealing the correspondence between long-standing mysteries in both fields: overflow metabolism and Giffen behaviour. Overflow metabolism, particularly known as the Warburg effect in cancer (9, 10), is a seemingly wasteful but ubiquitous strategy where cells utilize aerobic glycolysis instead of the more energetically-efficient oxidative phosphorylation (9–16), whereas Giffen behaviour is the unexpected consumer behaviour where a good is demanded more as its price rises (17, 18). We revealed that the general conditions for these phenomena are trade-off and complementarity, i.e., impossibility of substitution for different goods. This correspondence implies that oxidative phosphorylation is counterintuitively stimulated when its efficiency is decreased by metabolic perturbations like drug administration. Therefore, Giffen behaviour bridges the Warburg effect and the reverse and inverse Warburg effect (19–22). This highlights that application of microeconomics to metabolism can offer new predictions and paradigms for both biology and economics.
Nanoscale subcellular architecture revealed by multicolor 3D salvaged fluorescence imaging
Authors: Zhang Yongdeng , Schroeder Lena K. , Lessard Mark D. , Kidd Phylicia , Chung Jeeyun , Song Yuanbin , Benedetti Lorena , Li Yiming , Ries Jonas , De Camilli Pietro , Rothman James E. , Baddeley David , Bewersdorf Joerg 
Published: April 2019

AbstractCombining the molecular specificity of fluorescent probes with three-dimensional (3D) imaging at nanoscale resolution is critical for investigating the spatial organization and interactions of cellular organelles and protein complexes. We present a super-resolution light microscope that enables simultaneous multicolor imaging of whole mammalian cells at ~20 nm 3D resolution. We show its power for cell biology research with fluorescence images that resolved the highly convoluted Golgi apparatus and the close contacts between the endoplasmic reticulum and the plasma membrane, structures that have traditionally been the imaging realm of electron microscopy.One Sentence SummaryComplex cellular structures previously only resolved by electron microscopy can now be imaged in multiple colors by 4Pi-SMS.
Translocation of dense granule effectors across the parasitophorous vacuole membrane inToxoplasma-infected cells requires the activity of ROP17, a rhoptry protein kinase
Authors: Panas Michael W. , Ferrel Abel , Naor Adit , Tenborg Elizabeth , Lorenzi Hernan A. , Boothroyd John C. 
Published: April 2019

AbstractToxoplasma gondiitachyzoites co-opt host cell functions through introduction of a large set of rhoptry- and dense granule-derived effector proteins. These effectors reach the host cytosol through different means: direct injection for rhoptry effectors and translocation across the parasitophorous vacuolar membrane (PVM) for dense granule (GRA) effectors. The machinery that translocates these GRA effectors has recently been partially elucidated, revealing 3 components, MYR1, MYR2 and MYR3. To determine if other proteins might be involved, we returned to a library of mutants defective in GRA translocation and selected one with a partial defect, suggesting it might be in a gene encoding a new component of the machinery. Surprisingly, whole-genome sequencing revealed a missense mutation in a gene encoding a known rhoptry protein, a serine/threonine protein kinase known as ROP17. ROP17 resides on the host-cytosol side of the PVM in infected cells and has previously been known for its activity in phosphorylating and, thereby, inactivating host immunity-related GTPases. Here, we show that null or catalytically dead mutants of ROP17 are defective in GRA translocation across the PVM, but that translocation can be rescued “intrans"by ROP17 delivered by other tachyzoites infecting the same host cell. This strongly argues that ROP17’s role in regulating GRA translocation is carried out on the host-cytosolic side of the PVM, not within the parasites or lumen of the parasitophorous vacuole. This represents an entirely new way in which the different secretory compartments ofToxoplasmatachyzoites collaborate to modulate the host-parasite interaction.ImportanceWhenToxoplasmainfects a cell it establishes a protective parasitophorous vacuole surrounding it. While this vacuole provides protection, it also serves as a barrier to the export of parasite effector proteins that impact and take control of the host cell. Our discovery here that the parasite rhoptry protein, ROP17, is necessary for export of these effector proteins provides a distinct, novel function for ROP17 apart from its known role in protecting the vacuole. This will enable future research into ways in which we can prevent the export of effector proteins thereby preventingToxoplasmafrom productively infecting its animal and human hosts.
The genome of the endangered Dryas monkey provides new insights into the evolutionary history of the vervets
Authors: van der Valk T. , Gonda C. M. , Silegowa H. , Almanza S. , Sifuentes-Romero I. , Hart T. , Hart J. , Detwiler K. , Guschanski K. 
Published: April 2019

AbstractGenomic data can be a powerful tool for inferring ecology, behaviour and conservation needs of highly elusive species, particularly when other sources of information are hard to come by. Here we focus on the Dryas monkey (Cercopithecus dryas), an endangered primate endemic to the Congo Basin with cryptic behaviour and possibly less than 250 remaining individuals. Using whole genome sequencing data we show that the Dryas monkey represents a sister lineage to the vervets (Chlorocebus sp.) and has diverged from them around 1.4 million years ago with additional bi-directional gene flow ∼750,000 – ∼500,000 years ago that has likely involved the crossing of the Congo River. Together with evidence of gene flow across the Congo River in bonobos and okapis, our results suggest that the fluvial topology of the Congo River might have been more dynamic than previously recognised. Despite the presence of several homozygous loss-of-function mutations in genes associated with sperm mobility and immunity, we find high genetic diversity and low levels of inbreeding and genetic load in the studied Dryas monkey individual. This suggests that the current population carries sufficient genetic variability for long-term survival and might be larger than currently recognised. We thus provide an example of how genomic data can directly improve our understanding of highly elusive species.
Sensorimotor peak alpha frequency is a reliable biomarker of pain sensitivity
Authors: Furman Andrew J. , Prokhorenko Mariya , Keaser Michael L. , Zhang Jing , Chen Shuo , Mazaheri Ali , Seminowicz David A. 
Published: April 2019

AbstractPrevious research has observed that individuals with chronic pain demonstrate slower alpha band oscillations (8-12 Hz range) during resting electroencephalography (EEG) than do age-matched, healthy controls. While this slowing may reflect pathological changes within the brain that occur during the chronification of pain, an alternative explanation is that healthy individuals with slower alpha frequencies are more sensitive to prolonged pain, and by extension, more susceptible to developing chronic pain. To formally test this hypothesis, we examined the relationship between the pain-free, resting alpha frequency of healthy individuals and their subsequent sensitivity to two experimental models of prolonged pain, Phasic Heat Pain and Capsaicin Heat Pain, at two testing visits separated by 8 weeks on average (n = 61 Visit 1, n = 46 Visit 2). We observed that the speed of an individual’s pain-free alpha oscillations was negatively correlated with sensitivity to both prolonged pain tests and that this relationship was reliable across short (minutes) and long (weeks) timescales. Furthermore, we used the speed of pain-free alpha oscillations to successfully identify those individuals most sensitive to prolonged pain, which we also validated on data from a separate, independent study. These results suggest that alpha oscillation speed is a reliable biomarker of prolonged pain sensitivity with the potential to become a tool for prospectively identifying pain sensitivity in the clinic.
Iron is a ligand of SecA-like metal-binding domainsin vivo
Authors: Cranford-Smith Tamar , Jamshad Mohammed , Jeeves Mark , Chandler Rachael A. , Yule Jack , Robinson Ashley , Alam Farhana , Dunne Karl A. , Aponte Angarita Edwin H. , Alanazi Mashael , Carter Cailean , Henderson Ian R. , Lovett Janet E. , Winn Peter , Knowles Timothy , Huber Damon 
Published: April 2019

ABSTRACTThe ATPase SecA is an essential component of the bacterial Sec machinery, which transports proteins across the cytoplasmic membrane. Most SecA proteins contain a long C-terminal tail (CTT). InEscherichia coli, the CTT contains a structurally flexible linker domain and a small metal-binding domain (MBD). The MBD coordinates zinc via a conserved cysteine-containing motif and binds to SecB and ribosomes. In this study, we screened a high-density transposon library for mutants that affect the susceptibility ofE. colito sodium azide, which inhibits SecA-mediated translocation. Results from sequencing this library suggested that mutations removing the CTT makeE. coliless susceptible to sodium azide at subinhibitory concentrations. Copurification experiments suggested that the MBD binds to iron and that azide disrupts iron binding. Azide also disrupted binding of SecA to membranes. Two otherE. coliproteins that contain SecA-like MBDs, YecA and YchJ, also copurified with iron, and NMR spectroscopy experiments indicated that YecA binds iron via its MBD. Competition experiments and equilibrium binding measurements indicated that the SecA MBD binds preferentially to iron and that a conserved serine is required for this specificity. Finally, structural modelling suggested a plausible model for the octahedral coordination of iron. Taken together, our results suggest that SecA-like MBDs likely bind to ironin vivo.
Spatially and temporally distinct encoding of muscle and kinematic information in rostral and caudal primary motor cortex
Authors: Kolasinski James , Dima Diana C. , Mehler David M. A. , Stephenson Alice , Valadan Sara , Kusmia Slawomir , Rossiter Holly E. 
Published: April 2019

AbstractHand movements are controlled by neuronal networks in primary motor cortex (M1). The organising principle in M1 does not follow an anatomical body map, but rather a distributed representational structure in which motor primitives are combined to produce motor outputs. Both electrophysiological recordings in primates and human imaging data suggest that M1 encodes kinematic features of movements, such as joint position and velocity. However, M1 exhibits well-documented sensory responses to cutaneous and proprioceptive stimuli, raising questions regarding the origins of kinematic motor representations: are they relevant in top-down motor control, or are they an epiphenomenon of bottom-up sensory feedback during movement? Moreover, to what extent is information related to muscle activity encoded in motor cortex? Here we provide evidence for spatially and temporally distinct encoding of kinematic and muscle information in human M1 during the production of a wide variety of naturalistic hand movements. Using a powerful combination of high-field fMRI and MEG, a spatial and temporal multivariate representational similarity analysis revealed encoding of kinematic information from data glove recordings in more caudal regions of M1, over 200ms before movement onset. In contrast, patterns of muscle activity from EMG were encoded in more rostral motor regions later in the cycle of movement. Our spatial and temporal analysis provide compelling evidence that top-down control of dexterous movement engages kinematic representations in caudal regions of M1 prior to movement production; an area with direct cortico-motorneuronal connections. Muscle information encoded more rostrally in M1 was engaged later, suggestive of involvement in bottom-up signalling.
A Crispr Knockout Screen Identifies Foxf1 as a Suppressor of Colorectal Cancer Metastasis that Acts through Reduced mTOR Signalling
Authors: Lee Lennard , Woolley Connor , Starkey Thomas , Freeman-Mills Luke , Bassett Andrew , Franchini Fanny , Wang Lai Mun , Lewis Annabelle , Arnold Roland , Tomlinson Ian 
Published: April 2019

AbstractIntroductionA greater understanding of molecular mechanisms underlying metastasis is necessary for development of new strategies to prevent and treat cancer.MethodsWe performed a genome-wide CRISPR/Cas9 knockout screen in MC38 colorectal cancer (CRC) cells transplanted orthotopically into mice to identify genes that promote metastasis. We undertook focussed molecular analyses to identify mechanisms underlying metastasis.ResultsThe screen identified several gene knockouts over-represented in lung metastases, including Dptor (mTOR signalling) and Foxf1 (gastrointestinal tumour predisposition). We validate that loss of Foxf1 promotes metastasis, increased Foxf1 expression restrained cellular migration in-vitro and human CRC metastases express lower Foxf1 than paired primary tumours. Analysis of gene expression changes downstream of Foxf1 identified increased mTOR signalling as a possible mechanism of metastasis caused by Foxf1 loss, consistent with Dptor identification. We confirmed this mechanism demonstrating that mTOR inhibitor sirolimus reduced lung metastasis burden in xenografts.ConclusionMesenchymal Foxf1 plays a major role in intestinal development. We have shown for the first time, through an unbiased genetic screen, that reduced epithelial Foxf1 results in raised mTOR signalling and metastasis.Authorship statementLennard Lee-study concept and design, acquisition of data, analysis, interpretation of data, drafting of the manuscript, statistical analysis and obtained funding. Connor Woolley-acquisition of data, analysis and interpretation of data. Thomas Starkey-acquisition of data, analysis, interpretation of data, drafting of the manuscript. Luke Freeman-Mills-interpretation of data. Andrew Bassett-technical and material support. Fanny Fanchini-technical support. Lai Mun Wang-acquisition of data and study supervision. Annabelle Lewis-study supervision. Roland Arnold-analysis, interpretation of data, statistical analysis. Ian Tomlinson-study supervision and critical revision of the manuscript.Conflict of InterestThe authors whose names are listed above declare that they have no conflict of interest.
Discovery of functional alternatively splicedPKMtranscripts in human cancers
Authors: Li Xiangyu , Zhang Cheng , Kim Woonghee , Arif Muhammad , Gao Chunxia , Hober Andreas , Kotol David , Strandberg Linnéa , Forsström Björn , Sivertsson Åsa , Oksvold Per , Grøtli Morten , Sato Yusuke , Kume Haruki , Ogawa Seishi , Boren Jan , Nielsen Jens , Uhlen Mathias , Mardinoglu Adil 
Published: April 2019

ABSTRACTThe association of pyruvate kinase muscle type (PKM) with survival of cancer patients is controversial. Here, we focus on different transcripts ofPKMand investigate the association between their mRNA expression and the clinical survival of the patients in 25 different cancers. We find that the transcript encoding PKM2, and three other functional transcripts are prognostic in multiple cancers. Our integrative analysis shows that the functions of these four transcripts are highly conservative in different cancers. Next, we validate the prognostic effect of these transcripts in an independent kidney renal clear-cell carcinoma (KIRC) cohort and identify a prognostic signature which could distinguish high- and low-risk KIRC patients. Finally, we reveal the functional role of alternatively splicedPKMtranscripts in KIRC, and discover the protein products of different transcripts ofPKM. Our analysis demonstrated that alternatively spliced transcripts of not onlyPKMbut also other genes should be considered in cancer studies, since it may enable the discovery and targeting of the right protein product for development of the efficient treatment strategies.
PopTargs: A database for studying population evolutionary genetics of human microRNA target sites
Authors: Hatlen Andrea , Helmy Mohab , Marco Antonio 
Published: April 2019

ABSTRACTThere is an increasing interest in the study of polymorphic variants at gene regulatory motifs, including microRNA target sites. Understanding the effects of selective forces at specific microRNA target sites, together with other factors like expression levels or evolutionary conservation, requires the joint study of multiple datasets. We have compiled information from multiple sources and compare it with predicted microRNA target sites to built a comprehensive database for the study of microRNA targets in human populations. PopTargs is a web-based tool that allows the easy extraction of multiple datasets and the joint analyses of them, including allele frequencies, ancestral status, population differentiation statistics and site conservation. The user can also compare the allele frequency spectrum between two groups of target sites, and conveniently produce plots. The database can be easily expanded as new data becomes available and the raw database as well as code for creating new custom made databases are available for downloading. We also describe a few illustrative examples.Availability and implementationPoptargs is available athttp://poptargs.essex.ac.ukContactamarco.bio@gmail.com
The impact of population variation in the analysis of microRNA target sites
Authors: Helmy Mohab , Hatlen Andrea , Marco Antonio 
Published: April 2019

AbstractThe impact of population variation in the analysis of regulatory interactions is an underdeveloped area. MicroRNA target recognition occurs via pairwise complementarity. Consequently, a number of computational prediction tools have been developed to identify potential target sites, that can be further validated experimentally. However, as microRNA target predictions are done mostly considering a reference genome sequence, target sites showing variation among populations are neglected. Here we study variation at microRNA target sites in human populations and quantify their impact in microRNA target prediction. We found that African populations carry a significant number of potential microRNA target sites that are not detectable in the current human reference genome sequence. Some of these targets are conserved in primates and only lost in Out-of-Africa populations. Indeed, we identified experimentally validated microRNA/transcript interactions that are not detected in standard microRNA target prediction programs, yet they have segregating target alleles abundant in non-European populations. In conclusion, here we show that ignoring population diversity may leave out regulatory elements essential to understand disease and gene expression, particularly neglecting populations of African origin.
Experience-dependent coding of frequency-modulated trajectories by offsets in auditory cortex
Authors: Chong Kelly K , Dunlap Alex G , Kacsoh Dorottya B , Liu Robert C 
Published: April 2019

SUMMARYFrequency modulations are an inherent feature of many behaviorally relevant sounds, including vocalizations and music. Changing trajectories in a sound’s frequency often conveys meaningful information, which can be used to differentiate sound categories, as in the case of intonations in tonal languages. However, it is not clear what features of the neural responses in what parts of the auditory cortical pathway might be more important for conveying information about behaviorally relevant frequency modulations, and how these responses change with experience. Here we uncover tuning to subtle variations in frequency trajectories in mouse auditory cortex. Surprisingly, we found that auditory cortical responses could be modulated by variations in a pure tone trajectory as small as 1/24th of an octave. Offset spiking accounted for a significant portion of tuned responses to subtle frequency modulation. Offset responses that were present in the adult A2, but not those in Core auditory cortex, were plastic in a way that enhanced the representation of an acquired behaviorally relevant sound category, which we illustrate with the maternal mouse paradigm for natural communication sound learning. By using this ethologically inspired sound-feature tuning paradigm to drive auditory responses in higher-order neurons, our results demonstrate that auditory cortex can track much finer frequency modulations than previously appreciated, which allows A2 offset responses in particular to attune to the pitch trajectories that distinguish behaviorally relevant, natural sound categories.
GWAS of brain volume on 54,407 individuals and cross-trait analysis with intelligence identifies shared genomic loci and genes
Authors: Jansen Philip R , Nagel Mats , Watanabe Kyoko , Wei Yongbin , Savage Jeanne E , de Leeuw Christiaan A , van den Heuvel Martijn P , van der Sluis Sophie , Posthuma Danielle 
Published: April 2019

AbstractThe phenotypic correlation between human intelligence and brain volume (BV) is considerable (r≈0.40), and has been shown to be due to shared genetic factors1. To further examine specific genetic factors driving this correlation, we present genomic analyses of the genetic overlap between intelligence and BV using genome-wide association study (GWAS) results. First, we conducted the largest BV GWAS meta-analysis to date (N=54,407 individuals), followed by functional annotation and gene-mapping. We identified 35 genomic loci (27 novel), implicating 362 genes (346 novel) and 23 biological pathways for BV. Second, we used an existing GWAS for intelligence (N=269,867 individuals2), and estimated the genetic correlation (rg) between BV and intelligence to be 0.23. We show that the rg is driven by physical overlap of GWAS hits in 5 genomic loci. We identified 67 shared genes between BV and intelligence, which are mainly involved in important signaling pathways regulating cell growth. Out of these 67 we prioritized 32 that are most likely to have functional impact. These results provide new information on the genetics of BV and provide biological insight into BV’s shared genetic etiology with intelligence.