bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of missing values in untargeted MS-based metabolomics data and evaluation of missing data handling strategies
Authors: Do Kieu Trinh , Wahl Simone , Raffler Johannes , Molnos Sophie , Laimighofer Michael , Adamski Jerzy , Suhre Karsten , Strauch Konstantin , Peters Annette , Gieger Christian , Langenberg Claudia , Stewart Isobel D. , Theis Fabian J. , Grallert Harald , Kastenmüller Gabi , Krumsiek Jan 
Published: February 2018

AbstractBACKGROUNDUntargeted mass spectrometry (MS)-based metabolomics data often contain missing values that reduce statistical power and can introduce bias in epidemiological studies. However, a systematic assessment of the various sources of missing values and strategies to handle these data has received little attention. Missing data can occur systematically, e.g. from run day-dependent effects due to limits of detection (LOD); or it can be random as, for instance, a consequence of sample preparation.METHODSWe investigated patterns of missing data in an MS-based metabolomics experiment of serum samples from the German KORA F4 cohort (n = 1750). We then evaluated 31 imputation methods in a simulation framework and biologically validated the results by applying all imputation approaches to real metabolomics data. We examined the ability of each method to reconstruct biochemical pathways from data-driven correlation networks, and the ability of the method to increase statistical power while preserving the strength of established genetically metabolic quantitative trait loci.RESULTSRun day-dependent LOD-based missing data accounts for most missing values in the metabolomics dataset. Although multiple imputation by chained equations (MICE) performed well in many scenarios, it is computationally and statistically challenging. K-nearest neighbors (KNN) imputation on observations with variable pre-selection showed robust performance across all evaluation schemes and is computationally more tractable.CONCLUSIONMissing data in untargeted MS-based metabolomics data occur for various reasons. Based on our results, we recommend thatKNN-based imputation is performed on observations with variable pre-selection since it showed robust results in all evaluation schemes.Key messagesUntargeted MS-based metabolomics data show missing values due to both batch-specific LOD-based and non-LOD-based effects.Statistical evaluation of multiple imputation methods was conducted on both simulated and real datasets.Biological evaluation on real data assessed the ability of imputation methods to preserve statistical inference of biochemical pathways and correctly estimate effects of genetic variants on metabolite levels.KNN-based imputation on observations with variable pre-selection andK= 10 showed robust performance for all data scenarios across all evaluation schemes.
Viral-mediated optogenetic stimulation of peripheral motor nerves in non-human primates
Authors: Williams Jordan J. , Watson Alan M. , Vazquez Alberto L. , Schwartz Andrew B. 
Published: February 2018

AbstractObjectiveReanimation of muscles paralyzed by disease states such as spinal cord injury remains a much sought after therapeutic goal of neuroprosthetic research. Optogenetic stimulation of peripheral motor nerves expressing light-sensitive opsins is a promising approach to muscle reanimation that may overcome several drawbacks of traditional methods such as functional electrical stimulation (FES). However, the utility of these methods has only been demonstrated in rodents to date, while translation to clinical practice will likely first require demonstration and refinement of these gene therapy techniques in non-human primates.ApproachThree rhesus macaques were injected intramuscularly with either one or both of two optogenetic constructs (AAV6-hSyn-ChR2-eYFP and/or AAV6-hSyn-Chronos-eYFP) to transduce opsin expression in the corresponding nerves. Neuromuscular junctions were targeted for virus delivery using an electrical stimulating injection technique. Functional opsin expression was periodically evaluated up to 13 weeks post-injection by optically stimulating targeted nerves with a 472 nm fiber-coupled laser while recording electromyographic (EMG) responses.Main ResultsOne monkey demonstrated functional expression of ChR2 at 8 weeks post-injection in each of two injected muscles, while the second monkey briefly exhibited contractions coupled to optical stimulation in a muscle injected with the Chronos construct at 10 weeks. A third monkey injected only in one muscle with the ChR2 construct showed strong optically coupled contractions at 5 ½ weeks which then disappeared by 9 weeks. EMG responses to optical stimulation of ChR2-transduced nerves demonstrated graded recruitment relative to both stimulus pulse-width and light intensity, and were able to track stimulus trains up to 16 Hz. In addition, the EMG response to prolonged stimulation showed delayed fatigue over several minutes.SignificanceThese results demonstrate the feasibility of viral transduction of peripheral motor nerves for functional optical stimulation of motor activity in non-human primates, a variable timeline of opsin expression in a primate model closer to humans, and fundamental EMG response characteristics to optical nerve stimulation. Subsequently, they represent an important step in translating these optogenetic techniques as a clinically viable gene therapy.
Neuroligins mediate presynaptic maturation through brain-derived neurotrophic factor signaling
Authors: Petkova Andoniya , Gödecke Nina , Korte Martin , Dresbach Thomas 
Published: February 2018

AbstractMaturation is a process that allows synapses to acquire full functionality; failures in synaptic maturation may contribute to neurodevelopmental disorders. Neuroligins are postsynaptic cell-adhesion molecules essential for synapse maturation, but the underlying pathways are incompletely understood. Here, we show that maturational increases in active zone stability and synaptic vesicle recycling rely on the joint action of Neuroligins and brain-derived neurotrophic factor (BDNF). Applying BDNF to neuronal cultures mimicked the maturation-promoting effects of overexpressing the Neuroligin isoforms NL1 or NL2. Inhibiting BDNF signaling reduced the effects of NL1 and NL2 on presynaptic maturation and of NL2 on synapse formation. Applying BDNF to NL1-knockout mouse cultures rescued defective presynaptic maturation, indicating that BDNF acts downstream of NL1 and can restore presynaptic maturation at late stages of network development. Our data introduce BDNF as a novel and essential component in a transsynaptic pathway linking Neuroligin-mediated cell adhesion, neurotrophin action and presynaptic maturation.
A T7 phage factor required for managing RpoS inEscherichia coli
Authors: Tabib-Salazar Aline , Liu Bing , Barker Declan , Burchell Lynn , Qimron Udi , Matthews Steve J. , Wigneshweraraj Sivaramesh 
Published: February 2018

T7 development inEscherichia colirequires the inhibition of the housekeeping form of the bacterial RNA polymerase (RNAP), Eσ70, by two T7 proteins: Gp2 and Gp5.7. While the biological role of Gp2 is well understood, that of Gp5.7 remains to be fully deciphered. Here, we present results from functional and structural analyses to reveal that Gp5.7 primarily serves to inhibit EσS, the predominant form of the RNAP in the stationary phase of growth, which accumulates in exponentially growingE. colias a consequence of buildup of guanosine pentaphosphate ((p)ppGpp) during T7 development. We further demonstrate a requirement of Gp5.7 for T7 development inE. colicells in the stationary phase of growth. Our finding represents a paradigm for how some lytic phages have evolved distinct mechanisms to inhibit the bacterial transcription machinery to facilitate phage development in bacteria in the exponential and stationary phases of growth.Significance statementVirus that infect bacteria (phages) represent the most abundant living entities on the planet and many aspects of our fundamental knowledge of phage-bacteria relationships have been derived in the context of exponentially growing bacteria. In the case of the prototypicalEscherichia coliphage T7, specific inhibition of the housekeeping form of the RNA polymerase (Eσ70) by a T7 protein, called Gp2, is essential for the development of viral progeny. We now reveal that T7 uses a second specific inhibitor that selectively inhibits the stationary phase RNAP (EσS), which enables T7 to develop well in exponentially growing and stationary phase bacteria. The results have broad implications for our understanding of phage-bacteria relationships and therapeutic application of phages.
AnoniMME: Bringing Anonymity to the Matchmaker Exchange Platform for Rare Disease Gene Discovery
Authors: Oprisanu Bristena , Cristofaro Emiliano De 
Published: February 2018

AbstractMotivationAdvances in genome sequencing and genomics research are bringing us closer to a new era of personalized medicine, where healthcare can be tailored to the individual’s genetic makeup, and to more effective diagnosis and treatment of rare genetic diseases. Much of this progress depends on collaborations and access to data, thus, a number of initiatives have been introduced to support seamless data sharing. Among these, the Global Alliance for Genomics and Health has developed and operates a platform, called Matchmaker Exchange, which allows researchers to perform queries for rare genetic disease discovery over multiple federated databases. Queries include gene variations which are linked to rare diseases, and the ability to find other researchers that have seen or have interest in those variations is extremely valuable. Nonetheless, in some cases, researchers may be reluctant to use the platform since the queries they make (thus, what they are working on) are revealed to other researchers, and this creates concerns with respect to privacy and competitive advantage.ContributionsIn this paper, we present AnoniMME, a framework geared to enable anonymous queries within the Matchmaker Exchange platform. The framework, building on a cryptographic primitive called Reverse Private Information Retrieval, let researchers anonymously query the federated platform, in a multi-server setting—specifically, they write their query, along with a public encryption key, anonymously in a public database. Responses are also supported, so that other researchers can respond to queries by providing their encrypted contact details.Availability and Implementationhttps://github.com/bristena-op/AnoniMME.
Differential role of prefrontal and parietal cortices in controlling level of consciousness
Authors: Pal Dinesh , Dean Jon , Liu Tiecheng , Watson Christopher , Hudetz Anthony G. , Mashour George A. 
Published: February 2018

AbstractThere is current controversy regarding the role of prefrontal versus posterior cortices in consciousness. Clinical and correlative data have been used both to support and refute a causal role for prefrontal cortex in the level of consciousness, but a definitive relationship has not been demonstrated. We used anesthetic-induced unconsciousness as a model system to study the effect of cholinergic and noradrenergic stimulation of rat prefrontal and posterior parietal cortices on the level of consciousness. We demonstrate that cholinergic stimulation of prefrontal cortex, but not parietal cortical areas, restored wakefulness in rats despite continuous exposure to sevoflurane anesthesia. Noradrenergic stimulation of the prefrontal or parietal areas did not reverse the anesthetized state. We conclude that cholinergic mechanisms in prefrontal cortex can control the level of consciousness.One Sentence SummaryPrefrontal cholinergic stimulation restores consciousness in rats despite continuous exposure to sevoflurane anesthesia
Zinc(II) binding on human wild-type ISCU and Met140 variants modulates Fe-S complex activity
Authors: Fox Nicholas G. , Martelli Alain , Nabhan Joseph F. , Janz Jay , Borkowska Oktawia , Bulawa Christine , Yue Wyatt W. 
Published: February 2018

ABSTRACTThe human de novo iron-sulfur (Fe-S) assembly complex consists of the cysteine desulfurase NFS1, accessory protein ISD11, scaffold protein ISCU, and allosteric activator frataxin (FXN). FXN has been shown to bind the NFS1-ISD11-ISCU complex (SDU), to activate the desulfurase activity and thus Fe-S cluster biosynthesis. Conversely, in the absence of FXN, the NFS1-ISD11 (SD) complex was reported to be inhibited by the binding of recombinant ISCU. Here, we show that recombinant ISCU binds zinc(II) ion, and that the presence of zinc in as-isolated ISCU has impacts on the SDU desulfurase activity as measured by sulfide production. Indeed, the removal of this zinc(II) ion from ISCU causes a moderate but significant increase in activity compared to SD alone, and FXN can activate both zinc-depleted and zinc-bound forms of ISCU complexed to SD. Recent yeast studies have reported a substitution on the yeast ISCU orthologue Isu, at position Met141 (Met140 in human numbering of precursor protein) to Ile, Leu, Val, or Cys that could bypass the requirement of FXN for Fe-S cluster assembly and cell viability. Using recombinant human proteins, we report no significant differences in the biochemical and biophysical properties observed between wild-type and variants M140I, M140 L, and M140 V of ISCU. Importantly, in the absence of FXN, ISCU variants behaved like wild-type and did not stimulate the desulfurase activity of the SD complex. This study therefore identifies an important regulatory role for ISCU-bound zinc in modulation of the human Fe-S assembly system in vitro but no ‘FXN bypass’ effect on mutations at position Met140 in human ISCU.ABBREVIATIONSACPacyl carrier transfer proteinBLIbiolayer interferometryBSAbovine serum albuminCDcircular dichroismDMPDNN-dimethyl-p-phenylenediamineDSFdifferential scanning fluorimetryDTTdithiothreitol; EDTA, ethylenediaminetetracetic acidFe-Siron sulfurFRDAFriedreich’s ataxiaFXNfrataxinHEPES4-(2-hydroxyethyl)-1-piperazineethanesulfonic acidIPTGisopropyl β-D-1-thiogalactopyranosidePLPpyridoxal 5′-phosphateSDprotein complex composed of NFS 1 and ISD11SDUprotein complex composed of NFS 1, ISD11ISCUSDUF, protein complex composed of NFS 1, ISD11, ISCU, and frataxinTCAtrichloroacetic acidTCEPtris(2-carboxyethyl) phosphineTristris(hydroxymethyl)aminomethane
Diet Modifies Colonic Microbiota and CD4+ T Cell Repertoire to Trigger Flares in a Novel Model of Colitis Induced by IL-23
Authors: Chen Lili , He Zhengxiang , Iuga Alina Cornelia , Filho Sebastião N. Martins , Faith Jeremiah J. , Clemente Jose C. , Deshpande Madhura , Jayaprakash Anitha , Colombel Jean-Frederic , Lafaille Juan J. , Sachidanandam Ravi , Furtado Glaucia C. , Lira Sergio A. 
Published: February 2018

AbstractA wealth of experimental data points to immunological and environmental factors in the pathogenesis of inflammatory bowel disease (IBD). Here we study the role of IL-23, the microbiome, and the diet in the development of colitis. To promote IL-23 expression in vivo, we generated a mouse model in which IL-23 was conditionally expressed by CX3CR1+ myeloid cells, upon cyclic administration of tamoxifen in a specific diet (diet 2019). IL-23 expression induced an intestinal inflammatory disease that resembled ulcerative colitis in humans with cycles of acute disease and remission. The relapses were caused by the diet switch from the conventional diet used in our facility (diet 5053) to the diet 2019, and were not dependent on tamoxifen after the first cycle. The switch in the diet modified the microbiota, but did not alter the levels of IL-23. Colitis induction depended on the microbiota and required CD4 T lymphocytes. Colitis-inducing CD4+ T cells were found in the mesenteric lymph node and large intestine during remission and were able to trigger disease when transferred to lymphopenic mice, but only upon diet modification. The CD4 TCR repertoire in the diseased recipient Rag-/- mice had reduced diversity associated with the expansion of dominant T cell clones. These findings reveal a critical role for IL-23 in generation of a CD4+ T cell population in mice that is sensitive to a modification of intestinal bacterial flora subsequent to a dietary manipulation. Dietary changes occurring in the context of altered IL-23 expression may contribute to the onset and progression of IBD.
A folded viral noncoding RNA blocks host cell exoribonucleases through programmed remodeling of RNA structure
Authors: Steckelberg Anna-Lena , Akiyama Benjamin M. , Costantino David A. , Sit Tim L. , Nix Jay C. , Kieft Jeffrey S. 
Published: February 2018

AbstractFolded RNA elements that block processive 5′→3′ cellular exoribonucleases (xrRNAs) to produce biologically active viral non-coding RNAs were discovered in flaviviruses, potentially revealing a new mode of RNA maturation. However, it was unknown if this RNA structure-dependent mechanism exists elsewhere and if so, whether a singular RNA fold is required. Here, we demonstrate the existence of authentic RNA structure-dependent xrRNAs in dianthoviruses, plant-infecting viruses unrelated to animal-infecting flaviviruses. These novel xrRNAs have no sequence similarity to known xrRNAs, thus we used a combination of biochemistry and virology to characterize their sequence requirements and mechanism of stopping exoribonucleases. By solving the structure of a dianthovirus xrRNAs by x-ray crystallography, we reveal a complex fold that is very different from the flavivirus xrRNAs. However, both versions of xrRNAs contain a unique topological feature that is created by a different set of intramolecular contacts; this may be a defining structural feature of xrRNAs. Remarkably, the dianthovirus xrRNA can use ‘co-degradational remodeling,’ exploiting the exoribonuclease’s degradation-linked helicase activity to help form their resistant structure; such a mechanism has not previously been reported. Convergent evolution has created RNA structure-dependent exoribonuclease resistance in different contexts, which establishes it as a general RNA maturation mechanism and defines xrRNAs as an authentic functional class of RNAs.
Clonal Level Lineage Commitment Pathways of Hematopoietic Stem CellsIn Vivo
Authors: Lu Rong , Czechowicz Agnieszka , Seita Jun , Jiang Du , Weissman Irving L. 
Published: February 2018

ABSTRACTWhile hematopoietic stem cells (HSCs) have been extensively studied at the population level, little is known about the lineage commitment of individual clones. Here, we provide comprehensive maps ofin vivoHSC clonal development in mice under homeostasis and after depletion of the endogenous hematopoietic system. Under homeostasis, all donor-derived HSC clones regenerate blood homogeneously throughout all measured stages and lineages of hematopoiesis. In contrast, after the hematopoietic system has been depleted by irradiation or by an anti-ckit antibody, only a small fraction of donor-derived HSC clones differentiates while dominantly expanding and exhibiting lineage bias. We identified the cellular origins of clonal dominance and lineage bias, and uncovered the lineage commitment pathways that lead HSC clones to differential blood production. This study reveals surprising alterations in HSC regulation by irradiation, and identifies the key hematopoiesis stages that may be manipulated to control blood production and balance.SIGNIFICANCE STATEMENTHematopoietic stem cells (HSCs) sustain daily blood production through a complex step-wise lineage commitment process. In this work, we present the first comprehensive study of HSC lineage commitment at the clonal level and identify new HSC regulatory mechanisms that are undetectable by conventional population level studies. First, we uncover distinct HSC clonal pathways that lead to differential blood production and imbalances. Second, we reveal that HSC regulation under physiological conditions is strikingly different from that after injury. Third, we present a comprehensive map of HSC activities in vivo at the clonal level.
Multi-Omic Profiling Reveals the Opposing Forces of Excess Dietary Sugar and Fat on Liver Mitochondria Protein Acetylation and Succinylation
Authors: Meyer Jesse G. , Softic Samir , Basisty Nathan , Rardin Matthew J. , Verdin Eric , Gibson Bradford W. , Ilkayeva Olga , Newgard Christopher B. , Kahn C. Ronald , Schilling Birgit 
Published: February 2018

SummaryDietary macronutrient composition alters metabolism through several mechanisms, including post-translational modification (PTM) of proteins. To connect diet and molecular changes, here we performed short- and long-term feeding of mice with standard chow diet (SCD) and high-fat diet (HFD), with or without glucose or fructose supplementation, and quantified liver metabolites, 861 proteins, and 1,815 protein level-corrected mitochondrial acetylation and succinylation sites. Nearly half the acylation sites were altered by at least one diet; nutrient-specific changes in protein acylation sometimes encompass entire pathways. Although acetyl-CoA is an intermediate in both sugar and fat metabolism, acetyl-CoA had a dichotomous fate depending on its source; chronic feeding of dietary sugars induced protein hyperacetylation, whereas the same duration of HFD did not. Instead, HFD resulted in citrate accumulation, anaplerotic metabolism of amino acids, and protein hypo-succinylation. Together, our results demonstrate novel connections between dietary macronutrients, protein post-translational modifications, and regulation of fuel selection in liver.Graphical AbstractGraphical Abstract
The development of a competency model and its implementation in a power utility cooperative: an action research study
Authors: Brown LeAnn , George Babu , Mehaffey-Kultgen Candace 
Published: February 2018

Purpose
The purpose of this paper is to trace the development of a competency model in a medium-scale power utility company located in the Midwest USA.

Design/methodology/approach
The model is developed based on insights drawn from the literature, company documents, and primary interviews with the key company stakeholders. The research process was carried out according to the guidelines of action research methodology.

Findings
Competencies required for employees were identified and operationally defined. Existing competencies were inventoried and superimposed on the required competencies. Gaps in competency presence and proficiency levels were noticed. The competencies required for effective performance were distributed across different levels in the hierarchy, according to the competency needs of each hierarchical level.

Practical implications
Attempts to tie these competencies to employee selection, succession planning, performance appraisal, training need assessment, leadership development, etc., are currently ongoing. The case company has also initiated a competency-driven leadership development process. Possible adaptations of this model for similarly placed companies in other sectors are discussed.

Originality/value
This is an original case study based on primary data, conducted as action research.