bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atlas of Subcellular RNA Localization Revealed by APEX-seq
Authors: Fazal Furqan M. , Han Shuo , Kaewsapsak Pornchai , Parker Kevin R. , Xu Jin , Boettiger Alistair N. , Chang Howard Y. , Ting Alice Y. 
Published: October 2018

SUMMARYWe introduce APEX-seq, a method for RNA sequencing based on spatial proximity to the peroxidase enzyme APEX2. APEX-seq in nine distinct subcellular locales produced a nanometer-resolution spatial map of the human transcriptome, revealing extensive and exquisite patterns of localization for diverse RNA classes and transcript isoforms. We uncover a radial organization of the nuclear transcriptome, which is gated at the inner surface of the nuclear pore for cytoplasmic export of processed transcripts. We identify two distinct pathways of messenger RNA localization to mitochondria, each associated with specific sets of transcripts for building complementary macromolecular machines within the organelle. APEX-seq should be widely applicable to many systems, enabling comprehensive investigations of the spatial transcriptome.
Causally investigating cortical dynamics and signal processing by targeting natural system attractors with precisely timed stimulation
Authors: Lisitsyn Dmitriy , Ernst Udo A. 
Published: October 2018

1AbstractElectrical stimulation is a promising tool for interacting with neuronal dynamics to identify neural mechanisms that underlie cognitive function. Since effects of a single short stimulation pulse typically vary greatly and depend on the current network state, many experimental paradigms have rather resorted to continuous or periodic stimulation in order to establish and maintain a desired effect. However, such an approach explicitly leads to forced and ‘unnatural’ brain activity. Further, continuous stimulation can make it hard to parse the recorded activity and separate neural signal from stimulation artifacts. In this study we propose an alternate strategy: by monitoring a system in realtime, we use the existing preferred states or attractors of the network and to apply short and precise pulses in order to switch between its preferred states. When pushed into one of its attractors, one can use the natural tendency of the system to remain in such a state to prolong the effect of a stimulation pulse, opening a larger window of opportunity to observe the consequences on cognitive processing. To elaborate on this idea, we consider flexible information routing in the visual cortex as a prototypical example. When processing a stimulus, neural populations in the visual cortex have been found to engage in synchronized gamma activity. In this context, selective signal routing is achieved by changing the relative phase between oscillatory activity in sending and receiving populations (communication through coherence, CTC). In order to explore how perturbations interact with CTC, we investigate a biophysically realistic network exhibiting similar synchronization and signal routing phenomena. We develop a closed-loop stimulation paradigm based on the phase-response characteristics of the network and demonstrate its ability to establish desired synchronization states. By measuring information content throughout the model, we evaluate the effect of signal contamination caused by the stimulation in relation to the magnitude of the injected pulses and intrinsic noise in the system. Finally, we demonstrate that, up to a critical noise level, precisely timed perturbations can be used to artificially induce the effect of attention by selectively routing visual signals to higher cortical areas.
Rapid Tilt-Series Acquisition for Electron Cryotomography
Authors: Chreifi Georges , Chen Songye , Metskas Lauren Ann , Kaplan Mohammed , Jensen Grant J. 
Published: October 2018

AbstractUsing a new Titan Krios stage equipped with a single-axis holder, we developed two methods to accelerate the collection of tilt-series. We demonstrate a continuous-tilting method that can record a tilt-series in seconds (about 100x faster than current methods), but with loss of details finer than ∼4 nm. We also demonstrate a fast-incremental method that can record a tilt-series about 10x faster than current methods and with similar resolution. We characterize the utility of both methods in real biological electron cryotomography workflows. We identify opportunities for further improvements in hardware and software and speculate on the impact such advances could have on structural biology.
Unc 51–like autophagy-activating kinase (ULK1) mediates clearance of free α-globin in β-thalassemia
Authors: Lechauve Christophe , Keith Julia , Khandros Eugene , Fowler Stephanie , Mayberry Kalin , Freiwan Abdullah , Thom Christopher S. , Delbini Paola , Romero Emilio Boada , Zhang Jingjing , Motta Irene , Tillman Heather , Cappellini M. Domenica , Kundu Mondira , Weiss Mitchell J. 
Published: October 2018

AbstractErythroid maturation is coordinated to maximize the production of hemoglobin A heterotetramers (α2β2) and minimize the accumulation of potentially toxic free α- or β-globin subunits. In β-thalassemia, mutations in the β-globin gene cause a build-up of free α-globin, which forms intracellular precipitates that impair erythroid cell maturation and viability. Protein quality-control systems mitigate β-thalassemia pathophysiology by degrading toxic free α-globin. We show that loss of the Unc 51–like autophagy-activating kinase geneUlk1in β-thalassemic mice reduces autophagic clearance of α-globin in red cell precursors and exacerbates disease phenotypes, whereas inactivation of the canonical autophagy geneAtg5has minimal effects. Systemic treatment with rapamycin to inhibit the ULK1 inhibitor mTORC1 reduces α-globin precipitates and lessens pathologies in β-thalassemic mice, but not in those lackingUlk1. Similarly, rapamycin reduces free α-globin accumulation in erythroblasts derived from β-thalassemic patient CD34+hematopoietic progenitors. Our findings identify a new, drug-regulatable pathway for ameliorating β-thalassemia.One Sentence SummaryRapamycin alleviates β-thalassemia by stimulating ULK1-dependent autophagy of toxic free α-globin.
Human Handedness: Genetics, Microtubules, Neuropsychiatric Diseases and Brain Language Areas
Authors: Wiberg A. , Douaud G. , Ng M. , Al Omran Y. , Alfaro-Almagro F. , Marchini J. , Bennett D.L. , Smith S. , Furniss D. 
Published: October 2018

AbstractBackgroundThe skew in distribution of handedness is a uniquely human trait, and has fascinated researchers for centuries. The heritability of handedness is estimated at 25%, but defining genetic variants contributing to this trait has so far proved elusive.MethodsWe performed GWAS of self-reported handedness in UK Biobank, a prospective cohort study of ∼500,000 individuals. Furthermore, we investigated correlations between our associated SNPs and brain imaging-derived phenotypes (IDPs) from >9,000 individuals in UK Biobank, as well as between self-reported handedness and IDPs.ResultsOur association study of 38,322 left-handers vs 356,567 right-handers (excluding ambidextrous participants) revealed three genome-wide significant loci (rs199512, 17q21.31, p=4.1x10−9; rs45608532, 22q11.22, p=1.4x10−8; rs13017199, 2q34, p=3.3x10−8). In the imaging study, we found strong associations between rs199512 and diffusion MRI measures mainly in white matter tracts connecting language-related brain regions (p<2.0x10−6). Direct investigation between handedness and IDPs revealed numerous associations with functional connectivity between the same language-related areas of the brain. A second GWAS of non-right handers (n=44,631) vs right-handers (n=356,567) revealed an additional locus: rs3094128, 6p21.33, p=2.9x10−8. Three of the four associated loci (2q34, 17q21.31, 6p21.33) contain genes that encode microtubule-related proteins that are highly expressed in the brain: MAP2, MAPT and TUBB. These genes are strongly implicated in the pathogenesis of diseases that are known to affect an excess of left-handed people, including schizophrenia.ConclusionsThis is the first GWAS to identify genome-wide significant loci for human handedness in the general population, and the genes at these loci have biological plausibility in contributing to neurodevelopmental lateralization of brain organisation, which appears to predispose both to left-handedness and to certain neurodegenerative and psychiatric diseases.
Connect-seq to superimpose molecular on anatomical neural circuit maps
Authors: Hanchate Naresh K. , Lee Eun Jeong , Ellis Andria , Kondoh Kunio , Kuang Donghui , Basom Ryan , Trapnell Cole , Buck Linda B. 
Published: October 2018

AbstractThe mouse brain contains ~100 million neurons interconnected in a vast array of neural circuits. The identities and functions of individual neuronal components of most circuits are undefined. Here we describe a method, termed ‘Connect-seq’, which combines retrograde viral tracing and single cell transcriptomics to uncover the molecular identities of upstream neurons in a specific circuit and the signaling molecules they use to communicate. Connect-seq can generate a molecular map that can be superimposed on a neuroanatomical map to permit molecular and genetic interrogation of how the neuronal components of a circuit control its function. Application of this method to hypothalamic neurons controlling physiological responses to fear and stress reveal subsets of upstream neurons that express diverse constellations of signaling molecules and can be distinguished by their anatomical locations.
Doctoring knowledge or acknowledging doctors?
Authors: Carter Jennifer , Smith Erin F. , Gelves‐Gomez Francisco 
Published: October 2018

AbstractDoctoral forms of study are now diverse, although debate exists about whether ontological differences separate the research‐based Doctor of Philosophy (PhD) from alternative doctoral forms that contribute to professional practice. The purpose and processes of doctoral study and prevailing market logics that suit the knowledge economy affect the doctoral experience. Solutions entail relationality between the ideas that members of society hold about the ontology and purpose of the PhD and alternative doctoral forms, individual existential desires, and the materialities of the contemporary workplace. The PhD discursively contributes to both academic and professional becoming, with deep disciplinary mastery of threshold concepts. Disciplinary learning groups offer a critical and sometimes transforming experience. In addition to preparing the next generation of academics, the traditional PhD offers high‐level generic skills that are rare outside academia. In geography, especially, these skills are increasingly valued in society, not least when combined with diverse content that is highly relevant to contemporary global challenges. Institutions might help staff and candidates resist neoliberal tendencies for timely completions and offer a more appropriate learning experience, alongside ethical and transparent promotion of the purpose and practices of the doctoral experience. In time, such changes might signal a transformation influencing how all actors from society, the institution of higher education, supervisory staff, and doctoral candidates imagine doctoral and post‐doctoral work—“acknowledging” doctoral expertise and its societal value from both within and outside the academy.
HbA1c predicts long‐term postoperative mortality in patients with unknown glycemic status at admission for vascular surgery: An exploratory study
Authors: Hjellestad Iren D. , Søfteland Eirik , Husebye Eystein S. , Jonung Torbjørn 
Published: October 2018

AbstractBackgroundPeripheral arterial disease (PAD) and diabetes mellitus (DM) represent major public health challenges and are tightly associated. To facilitate early diagnosis, HbA1c has been implemented as the preferred diagnostic tool for the diagnosis of type 2 DM. In this study, we compared and evaluated HbA1c, fasting plasma glucose (FPG), and 2‐hour post‐load glucose values to determine which test best predicted mortality in patients with PAD.MethodsIn all, 273 PAD patients with unknown glycemic status admitted to Haukeland University Hospital for elective surgery between October 2006 and September 2007 were included in the study. All 273 patients underwent a standard oral glucose tolerance test (OGTT) in addition to determination of HbA1c; patients were then grouped into those with DM, intermediate hyperglycemia, and normoglycemia according to World Health Organization and International Expert Committee criteria.ResultsAll‐cause mortality was 40% over a 9‐year follow‐up period. After adjusting for age, sex, and relevant medication, HbA1c was a predictor for mortality (hazard ratio [HR] 1.54; 95% confidence interval [CI] 1.03‐2.32]; P = 0.04). The association did not achieve statistical significance in a fully adjusted Cox regression model, although the effect estimation of HbA1c on all‐cause mortality remained largely unchanged (HR 1.39; 95% CI 0.92‐2.09; P = 0.13). The OGTT was not a predictor of long‐term mortality.ConclusionsThe results indicate that HbA1c is a useful marker in the preoperative screening of patients of unknown glycemic status at the time of admission for vascular surgery, and may identify people at high risk of long‐term mortality following surgical treatment for PAD.
Electroencephalographic (EEG) density spectral array monitoring in children during sevoflurane anaesthesia: a prospective observational study
Authors: de Heer I. J. , Bouman S. J. M. , Weber F. 
Published: October 2018

SummaryElectroencephalographic density spectral array monitoring has been developed to facilitate the interpretation of unprocessed electroencephalogram signals. The primary aim of this prospective observational study, performed in a tertiary children's hospital, was to identify the clinical applicability and validity of density spectral array monitoring in infants and children during sevoflurane anaesthesia. We included 104 children, aged < 6 years, undergoing elective surgery during sevoflurane anaesthesia. We investigated the correlation between non‐steady state end‐tidal sevoflurane and the expression of the four electroencephalogram frequency bands β, α, θ and δ, representing density spectral array. Patients were divided into three age groups (< 6 months, 6–12 months, > 12 months). There was a significant correlation between end‐tidal sevoflurane and density spectral array in the age groups 6–12 months (p < 0.05) and 1–6 years (p < 0.0001). In infants < 6 months of age, the relative percentages of density spectral array did not correlate with end‐tidal sevoflurane. The main finding was that different end‐tidal concentrations of sevoflurane produce age‐dependent changes in the density spectral array power spectrum. In infants younger than 6 months‐old, α and β coherence are absent, whereas θ and δ oscillations have already emerged. In cases where anaesthesia was too deep, this presented as burst suppression on the electroencephalogram, θ disappeared, leaving the electroencephalographic activity in the δ range. Future research should address this issue, aiming to clarify whether the emergence of θ oscillations in infants helps to prevent sevoflurane overdosing.
A Hybrid Phase I-II/III Clinical Trial Design Allowing Dose Re-Optimization in Phase III
Authors: Chapple Andrew G. , Thall Peter F. 
Published: October 2018

Abstract
Conventionally, evaluation of a new drug, A, is done in three phases. Phase I is based on toxicity to determine a “maximum tolerable dose” (MTD) of A, phase II is conducted to decide whether A at the MTD is promising in terms of response probability, and if so a large randomized phase III trial is conducted to compare A to a control treatment, usually based on survival time or progression free survival time. It is widely recognized that this paradigm has many flaws. A recent approach combines the first two phases by conducting a phase I-II trial, which chooses an optimal dose based on both efficacy and toxicity, and evaluation of A at the selected optimal phase I-II dose then is done in a phase III trial. This paper proposes a new design paradigm, motivated by the possibility that the optimal phase I-II dose may not maximize mean survival time with A. We propose a hybridized design, which we call phase I-II/III, that combines phase I-II and phase III by allowing the chosen optimal phase I-II dose of A to be re-optimized based on survival time data from phase I-II patients and the first portion of phase III. The phase I-II/III design uses adaptive randomization in phase I-II, and relies on a mixture model for the survival time distribution as a function of efficacy, toxicity, and dose. A simulation study is presented to evaluate the phase I-II/III design and compare it to the usual approach that does not re-optimize the dose of A in phase III.
Omega‐3 fatty acids regulate plasticity in distinct hippocampal glutamatergic synapses
Authors: Aryal Sanjay , Hussain Suleman , Drevon Christian A. , Nagelhus Erlend , Hvalby Øyvind , Jensen Vidar , Walaas Sven Ivar , Davanger Svend 
Published: October 2018

AbstractDietary omega‐3 fatty acids accumulate and are actively retained in central nervous system membranes, mainly in synapses, dendrites and photoreceptors. Despite this selective enrichment, their impact on synaptic function and plasticity has not been fully determined at the molecular level. In this study, we explored the impact of omega‐3 fatty acid deficiency on synaptic function in the hippocampus. Dietary omega‐3 fatty acid deficiency for 5 months after weaning led to a 65% reduction in the concentration of docosahexaenoic acid in whole brain synaptosomal phospholipids with no impact on global dopaminergic or serotonergic turnover. We observed reduced concentrations of glutamate receptor subunits, including GluA1, GluA2 and NR2B, and synaptic vesicle proteins synaptophysin and synaptotagmin 1 in hippocampal synaptosomes of omega‐3 fatty acid‐deficient mice as compared to the omega‐3 fatty acid rich group. In contrast, an increased concentration of neuronal inositol 1,4,5‐trisphosphate‐receptor (IP3‐R) was observed in the deficient group. Furthermore, omega‐3 fatty acid deficiency reduced the long‐term potentiation (LTP) in stratum oriens of the hippocampal CA1 area, but not in stratum radiatum. Thus, omega‐3 fatty acids seem to have specific effects in distinct subsets of glutamatergic synapses, suggesting specific molecular interactions in addition to altering plasma membrane properties on a more global scale.
Spatial structure facilitates the accumulation and persistence of antibiotic‐resistant mutants in biofilms
Authors: France Michael T. , Cornea Ana , Kehlet‐Delgado Hanna , Forney Larry J. 
Published: October 2018

AbstractThe emergence and spread of antibiotic resistance in bacterial pathogens are a global crisis. Because many bacterial infections are caused by pathogens that reside in biofilms, we sought to investigate how biofilms influence the evolution of antibiotic resistance. We hypothesize that the inherent spatial structure of biofilms facilitates the accumulation and persistence of spontaneously evolved antibiotic‐resistant mutants. To test this, we tracked the frequency of mutants resistant to kanamycin and rifampicin in biofilm populations of Escherichia coli before, during, and after an antibiotic treatment regimen. Our results show that biofilms accumulate resistant mutants even in the absence of antibiotics. This resistance was found to be heritable and thus unlike the phenotypic plasticity of so‐called “persister cells” that have been shown to occur in biofilms. Upon exposure to an antibiotic, resistant mutants swept to high frequency. Following the conclusion of treatment, these resistant mutants remained at unexpectedly high frequencies in the biofilms for over 45 days. In contrast, when samples from kanamycin‐treated biofilms were used to found well‐mixed liquid cultures and propagated by serial transfer, the frequency of resistant cells dramatically decreased as they were outcompeted by sensitive clones. These observations suggest that the emergence of antibiotic resistance through spontaneous mutations in spatially structured biofilms may significantly contribute to the emergence and persistence of mutants that are resistant to antibiotics used to treat bacterial infections.
Tree stem bases are sources of CH4and N2O in a tropical forest on upland soil during the dry to wet season transition
Authors: Welch Bertie , Gauci Vincent , Sayer Emma J. 
Published: October 2018

AbstractTropical forests on upland soils are assumed to be a methane (CH4) sink and a weak source of nitrous oxide (N2O), but studies of wetland forests have demonstrated that tree stems can be a substantial source of CH4, and recent evidence from temperate woodlands suggests that tree stems can also emit N2O. Here, we measured CH4and N2O fluxes from the soil and from tree stems in a semi‐evergreen tropical forest on upland soil. To examine the influence of seasonality, soil abiotic conditions and substrate availability (litter inputs) on trace greenhouse gas (GHG) fluxes, we conducted our study during the transition from the dry to the wet season in a long‐term litter manipulation experiment in Panama, Central America. Trace GHG fluxes were measured from individual stem bases of two common tree species and from soils beneath the same trees. Soil CH4fluxes varied from uptake in the dry season to minor emissions in the wet season. Soil N2O fluxes were negligible during the dry season but increased markedly after the start of the wet season. By contrast, tree stem bases emitted CH4and N2O throughout the study. Although we observed no clear effect of litter manipulation on trace GHG fluxes, tree species and litter treatments interacted to influence CH4fluxes from stems and N2O fluxes from stems and soil, indicating complex relationships between tree species traits and decomposition processes that can influence trace GHG dynamics. Collectively, our results show that tropical trees can act as conduits for trace GHGs that most likely originate from deeper soil horizons, even when they are growing on upland soils. Coupled with the finding that the soils may be a weaker sink for CH4than previously thought, our research highlights the need to reappraise trace gas budgets in tropical forests.