bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of electrocorticographic seizure features predicts response to closed-loop brain stimulation
Authors: Kokkinos Vasileios , Sisterson Nathaniel D. , Wozny Thomas A. , Richardson R. Mark 
Published: September 2018

AbstractWhy does closed-loop invasive brain stimulation improve seizure control in some patients with epilepsy, but not others? The RNS System, the only FDA-approved bi-directional brain-computer interface, has been shown to improve seizure control in patients with refractory epilepsy, although the mechanisms behind this success are undefined. We analyzed recordings from the RNS System and discovered two main categories of electrophysiological signatures of stimulation-induced modulation of the seizure network. Direct effects included ictal inhibition and early frequency modulation but did not correlate with improved clinical outcomes. Only indirect effects, those occurring remote from triggered stimulation, predicted improved clinical outcomes. These indirect effects, which included spontaneous ictal inhibition, frequency modulation, fragmentation, and ictal duration modulation, may reflect progressive local epileptogenic network compartmentalization that hinders the spread of pathological synchrony from recruiting neuronal populations. Our findings suggest that responsiveness to RNS may be explained by chronic stimulation-induced modulation of seizure network activity, rather than direct effects on each detected seizure.
Field evaluation of malachite green loop-mediated isothermal amplification as a malaria parasite detection tool in a health post in Roraima state, Brazil
Authors: Kudyba Heather M. , Louzada Jaime , Ljolje Dragan , Kudyba Karl A. , Muralidharan Vasant , Oliveira-Ferreira Joseli , Lucchi Naomi W. 
Published: September 2018

ABSTRACTMalaria is a debilitating parasitic disease that causes significant morbidity and mortality. Microscopic detection of parasites is currently the “gold standard” diagnostic. This technique is limited in its ability to detect low-density infections, is time consuming, and requires a highly trained microscopist. Malaria epidemiological surveillance studies especially aimed at the detection of low-density infection and asymptomatic cases will require more sensitive and user-friendly tools. We have shown previously that the molecular-based, colorimetric malachite green loop-mediated isothermal amplification (MG-LAMP) assay is a valuable tool for diagnosing malaria infection in a laboratory setting. In this study, we field evaluated this assay in a malaria diagnostic post in Roraima, Brazil. We prospectively collected 91 patient samples and performed microscopy, MG-LAMP, and real-time PCR (PET-PCR) to detect Plasmodium infection. Two independent readers were used to score the MG-LAMP tests to assess whether the sample was positive (blue/green) or negative (clear). There was 100% agreement between the two readers (Kappa=1). All tests detected 33 positive samples, but both the MG-LAMP and PET-PCR detected 6 and 7 more positive samples, respectively. The PET-PCR assay detected 6 mixed infections (defined as infection with both P. falciparum and P. vivax) while microscopy detected one and MG-LAMP detected two of these mixed infections. Microscopy did not detect any Plasmodium infection in 26 of the enrolled asymptomatic cases while MG-LAMP detected five and PET-PCR assay three positive cases. Overall, MG-LAMP provided a simpler and user-friendly molecular method for malaria diagnosis that is more sensitive than microscopy. Additionally, MG- LAMP has the capacity to test 38 samples per run (one hour), allowing for the screening of large number of samples which is appealing when large-scale studies are necessary e.g. in community surveillance studies. The current MG-LAMP assay was limited in its ability to detect mixed infection when compared to the PET-PCR, but otherwise proved to be a powerful tool for malaria parasite detection in the field and opens new perspectives in the implementation of surveillance studies in malaria elimination campaigns.
SeqTailor: a user-friendly webserver for the extraction of DNA or protein sequences from next-generation sequencing data
Authors: Zhang Peng , Boisson Bertrand , Casanova Jean-Laurent , Abel Laurent , Itan Yuval 
Published: September 2018

ABSTRACTHuman whole-genome sequencing generally reveals about 4,000,000 genetic variants, including 20,000 coding variants, in each individual studied. These data are mostly stored as VCF-format files. Although many variant analysis methods accept VCF files as input, many other tools require DNA or protein sequences, particularly for splicing prediction, sequence alignment, phylogenetic analysis, and structure prediction. However, there is currently no existing online tool for extracting DNA or protein sequences for genomic variants from VCF files with user-defined parameters in a user-friendly, efficient, and standardized manner. We developed the SeqTailor webserver to bridge this gap. It can be used for the rapid extraction of (1) DNA sequences around genetic variants, with customizable window sizes, from the hg19 or hg38 human reference genomes; and (2) protein sequences encoded by the DNA sequences around genetic variants, with built-in SnpEff annotation and customizable window sizes, from human canonical transcripts. The SeqTailor webserver streamlines the sequence extraction process, and accelerates the analysis of genetic variant data with software requiring DNA or protein sequences. SeqTailor will facilitate the study of human genomic variation, by increasing the feasibility of sequence-based analysis and prediction. The SeqTailor webserver is freely available from http://shiva.rockefeller.edu/SeqTailor/.
Dissecting the sharp response of a canonical developmental enhancer reveals multiple sources of cooperativity
Authors: Park Jeehae , Estrada Javier , Johnson Gemma , Ricci-Tam Chiara , Bragdon Meghan , Shulgina Yekaterina , Cha Anna , Gunawardena Jeremy , DePace Angela H. 
Published: September 2018

AbstractDevelopmental enhancers integrate graded concentrations of input transcription factors (TFs) to create sharp gene expression boundaries. Here we examine the hunchback P2 (HbP2) enhancer which drives a sharp expression pattern in the Drosophila blastoderm embryo in response to the transcriptional activator Bicoid (Bcd). We systematically interrogate cis and transfactors that influence the shape and position of expression driven by HbP2, and find that the prevailing model, based on cooperative binding of Bcd to HbP2 is not adequate. We demonstrate that other proteins, such as pioneer factors, mediator and histone modifiers influence the shape and position of the HbP2 expression pattern. By comparing our results to theory, we assess how higher-order cooperativity and energy expenditure impact boundary location and sharpness. Our results emphasize that the bacterial view of transcription regulation, where pairwise interactions between regulatory proteins dominate, must be re-examined in animals, where multiple molecular mechanisms collaborate to shape the gene regulatory function.
Recovery and analysis of transcriptome subsets from pooled single-cell RNA-seq libraries
Authors: Riemondy Kent A. , Ransom Monica , Alderman Christopher , Gillen Austin E. , Fu Rui , Finlay-Schultz Jessica , Kirkpatrick Gregory , Paola Di Jorge , Kabos Peter , Sartorius Carol A. , Hesselberth Jay R. 
Published: September 2018

ABSTRACTSingle-cell RNA sequencing (scRNA-seq) methods generate sparse gene expression profiles for thousands of single cells in a single experiment. The information in these profiles is sufficient to classify cell types by distinct expression patterns but the high complexity of scRNA-seq libraries often prevents full characterization of transcriptomes from individual cells. To extract more focused gene expression information from scRNA-seq libraries, we developed a strategy to physically recover the DNA molecules comprising transcriptome subsets, enabling deeper interrogation of the isolated molecules by another round of DNA sequencing. We applied the method in cell-centric and gene-centric modes to isolate cDNA fragments from scRNA-seq libraries. First, we resampled the transcriptomes of rare, single megakaryocytes from a complex mixture of lymphocytes and analyzed them in a second round of DNA sequencing, yielding up to 20-fold greater sequencing depth per cell and increasing the number of genes detected per cell from a median of 1,313 to 2,002. We similarly isolated mRNAs from targeted T cells to improve the reconstruction of their VDJ-rearranged immune receptor mRNAs. Second, we isolatedCD3DmRNA fragments expressed across cells in a scRNA-seq library prepared from a clonal T cell line, increasing the number of cells with detectedCD3Dexpression from 59.7% to 100%. Transcriptome resampling is a general approach to recover targeted gene expression information from single-cell RNA sequencing libraries that enhances the utility of these costly experiments, and may be applicable to the targeted recovery of molecules from other single-cell assays.
Mutant p53 triggers a dynamin-1/APPL1 endosome feedback loop that regulates β1 integrin recycling and migration
Authors: Lakoduk Ashley M. , Roudot Philippe , Mettlen Marcel , Grossman Heather M. , Schmid Sandra L. , Chen Ping-Hung 
Published: September 2018

ABSTRACTMultiple mechanisms contribute to cancer cell progression and metastatic activity, including changes in endocytic trafficking and signaling of cell surface receptors. We report that gain-of-function (GOF) mutant p53 expression enhances β integrin and EGF receptor recycling and increases cell migration by triggering a positive feedback loop involving the activation of dynamin-1 (Dyn1) and accumulation of a spatially-restricted subpopulation of APPL1-positive ‘perimeter’ endosomes. DNM1 is upregulated at both the mRNA and protein levels in a manner dependent on expression of GOF mutant p53. Perimeter APPL1 endosomes are required for rapid recycling of EGFR and β1 integrins and modulate Akt signaling and Dyn1 activation to create the positive feedback loop that culminates in increased focal adhesion turnover and cell migration. Thus, Dyn1- and Akt-dependent perimeter APPL1 endosomes function as a nexus, integrating signaling and receptor trafficking, that can be co-opted by cancer cells for mutant p53-driven migration and invasion.
The entopeduncular nucleus drives lateral habenula responses to negative but not positive or neutral affective stimuli
Authors: Li Hao , Pullmann Dominika , Jhou Thomas C. 
Published: September 2018

AbstractLateral habenula (LHb) neurons are activated by negative motivational stimuli and play key roles in the pathophysiology of depression. Early reports indicated the possibility that rostral entopeduncular nucleus (rEPN) neurons drive these LHb responses, but this influence remains untested. We find that both rEPN and LHb neurons in rats exhibit similar activation/inhibition patterns after negative/positive motivational stimuli, but that the rEPN influence on LHb firing is surprisingly selective. Temporary rEPN inactivation decreases LHb basal and burst firing, and eliminates LHb responses to footshock-predictive cues occurring 40-100ms but not 10-30ms post-stimulus, nor on responses to positive/neutral motivational stimuli. Additionally, rEPN inactivation partially but not fully reduces LHb responses to signaled footshocks, while excitotoxic rEPN lesions only partially diminish footshock-induced cFos in the LHb and its rostromedial tegmental nucleus targets. Together, our findings indicate an important but selective role of the rEPN in driving LHb responses to motivational stimuli.
Accounting for ambiguity in ancestral sequence reconstruction
Authors: Oliva A. , Pulicani S. , Lefort V. , Bréhélin L. , Guindon S. 
Published: September 2018

AbstractThe reconstruction of ancestral genetic sequences from the analysis of contemporaneous data is a powerful tool to improve our understanding of molecular evolution. Various statistical criteria defined in a phylogenetic framework can be used to infer nucleotide, aminoa-cid or codon states at internal nodes of the tree, for every position along the sequence. These criteria generally select the state that maximises (or minimises) a given criterion. Although it is perfectly sensible from a statistical perspective, that strategy fails to convey useful information about the level of uncertainty associated to the inference. The present study introduces a new criterion for ancestral nucleotide reconstruction that selects a single state whenever the signal conveyed by the data is strong, and a combination of multiple states otherwise. Simulations demonstrate the benefit of this approach with a substantial increase in the accuracy of ancestral sequence reconstruction without significantly compromising on the precision of the solutions returned.
Acute inhibition of heterotrimeric kinesin-2 function reveals mechanisms of intraflagellar transport in mammalian cilia
Authors: Engelke Martin F. , Waas Bridget , Kearns Sarah E. , Suber Ayana , Boss Allison , Allen Benjamin L. , Verhey Kristen J. 
Published: September 2018

ABSTRACTThe trafficking of components within cilia, called intraflagellar transport (IFT), is powered by kinesin-2 and dynein-2 motors. Loss of function in any subunit of the heterotrimeric KIF3A/KIF3B/KAP kinesin-2 motor prevents ciliogenesis in mammalian cells and has hindered an understanding of how kinesin-2 motors function in IFT. We used a chemical-genetic approach to engineer an inhibitable KIF3A/KIF3B (i3A/i3B) kinesin-2 motor that is capable of rescuing WT motor function inKif3a/Kif3bdouble-knockout cells. Inhibitor addition blocks ciliogenesis or, if added to ciliated cells, blocks IFT within two minutes, which leads to a complete loss of primary cilia within six hours. The kinesin-2 family members KIF3A/KIF3C and KIF17 cannot rescue ciliogenesis inKif3a/Kif3bdouble-knockout cells nor delay the disassembly of full-formed cilia upon i3A/i3B inhibition. These data suggest that KIF3A/KIF3B/KAP is the sole and essential motor for cilia assembly and function in mammalian cells, indicating a species-specific adaptation of kinesin-2 motors for IFT function.
Trafficking of Cholesterol from Lipid Droplets to Mitochondria in Bovine Luteal Cells: Acute Control of Progesterone Synthesis1
Authors: Plewes Michele R. , Cordes Crystal , Przgrodzka Emilia , Talbott Heather , Wood Jennifer , Cupp Andrea , Davis John S. 
Published: September 2018

AbstractThe corpus luteum (CL) is a transient endocrine gland that synthesizes and secretes the steroid hormone, progesterone. Progesterone biosynthesis is a complex process, converting cholesterol via a series of enzymatic reactions, into progesterone. Lipid droplets in luteal cells store cholesterol in the form of cholesterol esters, which can be utilized for steroidogenesis. In small luteal cells, luteinizing hormone (LH) increases intracellular cAMP concentrations leading to activation of protein kinase A (PKA), which phosphorylates downstream proteins, such as hormone sensitive lipase (HSL). Phosphorylation of HSL at Ser563 leads to increased HSL activation and association with lipid droplets, events which theoretically release cholesterol, which can be used for progesterone synthesis. Bovine CL were obtained from a local abattoir, dispersed, and luteal cells were enriched for SLC via centrifugal elutriation. Our results reveal that LH, forskolin, and cAMP induce HSL phosphorylation at Ser563and Ser660. Moreover, inhibiting HSL activity attenuates LH-induced P4 synthesis. Confocal analysis revealed that LH stimulates translocation of HSL to lipid droplets and mitochondria. Furthermore, LH increased trafficking of cholesterol from the lipid droplets to the mitochondria which was dependent on both PKA and HSL activation. These results demonstrate cholesterol stored in lipid droplets are utilized for LH-induced progesterone biosynthesis. Likewise, PKA-induced activation of HSL is required for release and trafficking of cholesterol from the lipid droplets to the mitochondria. Taken together, these findings support a role for a PKA/HSL signaling pathway in response to LH and demonstrate the dynamic relationship between PKA, HSL, and the lipid droplets in the synthesis of progesterone.HighlightsLH and PKA induce HSL phosphorylation at Ser563and Ser660HSL is required for optimal LH-induced P4 synthesisLH stimulates translocation of HSL to lipid droplets and mitochondriaLH stimulated trafficking of cholesterol from lipid droplets to mitochondria
Loss of TLE3 Promotes Mitochondrial Program in Beige Adipocytes and Improves Glucose Metabolism
Authors: Pearson Stephanie , Loft Anne , Rahbhandari Prashant , Simcox Judith , Lee Sanghoon , Donato Anthony , Tontonoz Peter , Mandrup Susanne , Villanueva Claudio J. 
Published: September 2018

AbstractProlonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue are not well understood. Here we demonstrate that the transcriptional coregulator TLE3 is induced with aging and inhibits mitochondrial gene expression in beige adipocytes. Conditional deletion of TLE3 in adipocytes prevents age- and diet-induced weight gain by promoting mitochondrial oxidative metabolism and increasing energy expenditure, thereby improving glucose control. Using chromatin immunoprecipitation and deep sequencing we found that TLE3 occupies distal enhancers in proximity to nuclear-encoded mitochondrial genes and that many of these enhancers are also enriched for EBF transcription factors. TLE3 interacts with EBF2 and blocks its ability to promote the thermogenic transcriptional program. Collectively, these studies demonstrate that TLE3 mediates age-dependent beige adipose thermogenic decline through inhibition of EBF2 transcriptional activity. Inhibition of TLE3 may provide a novel therapeutic approach for obesity and diabetes.
Comprehensive Genomic Characterization of Breast Tumors with BRCA1 and BRCA2 Mutations
Authors: Lal Avantika , Ramazzotti Daniele , Weng Ziming , Liu Keli , Ford James M. , Sidow Arend 
Published: September 2018

AbstractBackgroundGermline mutations in the BRCA1 and BRCA2 genes predispose carriers to breast and ovarian cancer, and there remains a need to identify the specific genomic mechanisms by which cancer evolves in these patients. Here we present a systematic genomic analysis of breast tumors with BRCA1 and BRCA2 mutations.MethodsWe analyzed genomic data from breast tumors, with a focus on comparing tumors with BRCA1/BRCA2 gene mutations with common classes of sporadic breast tumors.ResultsWe identify differences between BRCA-mutated and sporadic breast tumors in patterns of point mutation, DNA methylation and structural variation. We show that structural variation disproportionately affects tumor suppressor genes and identify specific driver gene candidates that are enriched for structural variation.ConclusionsCompared to sporadic tumors, BRCA-mutated breast tumors show signals of reduced DNA methylation, more ancestral cell divisions, and elevated rates of structural variation that tend to disrupt highly expressed protein-coding genes and known tumor suppressors. Our analysis suggests that BRCA-mutated tumors are more aggressive than sporadic breast cancers because loss of the BRCA pathway causes multiple processes of mutagenesis and gene dysregulation.
The unspeakable truth of accounting
Authors: Bassnett Susan , Frandsen Ann-Christine , Hoskin Keith 
Published: September 2018

PurposeThe purpose of this paper is to investigate accounting as first visible-sign statement form, and also as the first writing, and analyse its systematic differences, syntactic and semantic, from subsequent speech-following (glottographic) writing forms. The authors consider how accounting as non-glottographic (and so “unspeakable”) writing form renders “glottography” a “subsystem of writing” (Hyman, 2006), while initiating a mode of veridiction which always and only names and counts, silently and synoptically. The authors also consider the translation of this statement form into the graphs, charts, equations, etc., which are central to the making of modern scientific truth claims, and to remaking the boundaries of “languaging” and translatability.Design/methodology/approachAs a historical–theoretical study, this draws on work reconceptualising writing vs speech (e.g. Harris, 1986; 2000), the statement vs the word (e.g. Foucault, 1972/2002) and the parameters of translation (e.g. Littau, 2016) to re-think the conceptual significance of accounting as constitutive of our “literate modes” of thinking, acting and “languaging in general”.FindingsSpecific reflections are offered on how the accounting statement, as mathematically regularised naming of what “ought” to be counted, is then evaluated against what is counted, thus generating a first discourse of the norm and a first accounting-based apparatus for governing the state. The authors analyse how the non-glottographic statement is constructed and read not as linear flow of signs but as simulacrum; and on how the accounting statement poses both the practical issue of how to translate non-linear flow statements, and the conceptual problem of how to think this statement form’s general translatability, given its irreducibility to the linear narrative statement form.Originality/valueThe paper pioneers in approaching accounting as statement form in a way that analyses the differences that flow from its non-glottographic status.
SLAPPing accountability out of the public sphere
Authors: Murphy Daniel , Moerman Lee 
Published: September 2018

PurposeThe purpose of this paper is to investigate the disruption to civic accountability by strategic corporate action in the form of SLAPP suits.Design/methodology/approachThis paper provides empirical evidence of the discursive processes underpinning participatory and emancipatory accountability regimes through the lens of deliberative democracy and the Habermasian ideal of the public sphere.FindingsWithin this paper, it is argued that the strategic use of SLAPPs by corporations presents a danger to both mechanistic and virtuous forms of accountability regardless of what deliberative democratic theory is adopted. Habermas’ theory of communicative action and notion of the “public sphere” is utilised to demonstrate how SLAPPs can result in the colonisation of public discursive arenas to prevent others providing alternative (in form) and counter (in view) accounts of corporate behaviour and thus act to limit opportunities for corporate accountability.Social implicationsThis paper throws light on a practice being utilised by corporations to limit public participation in democratic and participatory accountability processes. Strategic use of SLAPPs limit the “ability” for citizens to provide an alternative “account” of corporate behaviour.Originality/valueThis paper is original in that it analyses the impact on accountability of strategic corporate practice of issuing SLAPP suits to “chill” public political discussion and limit protest about issues of social and civic importance. The paper extends the critical accounting literature into improving dialogic and participatory accountability regimes.