bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bayesian inference of transcription dynamics from population snapshots of single-molecule RNA FISH in single cells
Authors: Gómez-Schiavon Mariana , Chen Liang-Fu , West Anne E. , Buchler Nicolas E. 
Published: February 2017

AbstractSingle-molecule RNA fluorescencein situhybridization (smFISH) provides unparalleled resolution on the abundance and localization of nascent and mature transcripts in single cells. Gene expression dynamics are typically inferred by measuring mRNA abundance in small numbers of fixed cells sampled from a population at multiple time-points after induction. The sparse data that arise from the small number of cells obtained using smFISH present a challenge for inferring transcription dynamics. Here, we developed a computational pipeline (BayFish) to infer kinetic parameters of gene expression from smFISH data at multiple time points after induction. Given an underlying model of gene expression, BayFish uses a Monte Carlo method to estimate the Bayesian posterior probability of the model parameters and quantify the parameter uncertainty given the observed smFISH data. We tested BayFish on smFISH measurements of the neuronal activity inducible geneNpas4in primary neurons. We showed that a 2-state promoter model can recapitulateNpas4dynamics after induction and we inferred that the transition rate from the promoter OFF state to the ON state is increased by the stimulus.Author SummaryGene expression can exhibit cell-to-cell variability due to the stochastic nature of biochemical reactions. Single cell assays (e.g. smFISH) directly quantify stochastic gene expression by measuring the number of active promoters and transcripts per cell in a population of cells. The data are distributions and their shape and time-evolution contain critical information on the underlying process of gene expression. Recent work has combined models of stochastic gene expression with maximum likelihood methods to infer kinetic parameters from smFISH distributions. However, these approaches do not provide a probability distribution or likelihood of model parameters inferred from the smFISH data. This information is useful because it indicates which parameters are loosely constrained by the data and suggests follow up experiments. We developed a suite of MATLAB programs (BayFish) that estimate the Bayesian posterior probability of model parameters from smFISH data. The user specifies an underlying model of stochastic gene expression with unknown parameters (θ) and provides smFISH data (Y). BayFish uses a Monte Carlo algorithm to estimate the Bayesian posterior probabilityP(θ|Y) of model parameters. BayFish is easily modified and can be applied to other models of stochastic gene expression and smFISH data sets.
Long-term taxonomic and functional divergence from donor bacterial strains following fecal microbiota transplantation in immunocompromised patients
Authors: Moss Eli L. , Falconer Shannon B. , Tkachenko Ekaterina , Wang Mingjie , Systrom Hannah , Mahabamunuge Jasmin , Relman David A. , Hohmann Elizabeth L. , Bhatt Ami S. 
Published: February 2017

AbstractImmunocompromised individuals are at high risk of developing Clostridium difficile-associated disease (CDAD). Fecal microbiota transplantation (FMT) is a highly effective therapy for refractory or recurrent CDAD and, despite safety concerns, has recently been offered to immunocompromised patients. We investigated the genomics of bacterial composition following FMT in immunocompromised patients over a 1-year period. Metagenomic, strain and gene-level bacterial dynamics were characterized in two CDAD-affected hematopoietic stem cell (HCT) recipients following FMT. We found alterations in gene content, including loss of virulence and antibiotic resistance genes. These alterations were accompanied by long-term bacterial divergence at the species and strain levels. Our findings suggest limited durability of the specific bacterial consortium introduced with FMT and indicate that alterations of the functional potential of the microbiome are more complex than can be inferred by taxonomic information alone. Our observation that FMT alone cannot induce long-term donor-like alterations of the microbiota of HCT recipients suggests that FMT cannot indefinitely supersede environmental and/or host factors in shaping bacterial composition.
Comprehensive Analysis of Constraint on the Spatial Distribution of Missense Variants in Human Protein Structures
Authors: Sivley R. Michael , Kropski Jonathan , Sheehan Jonathan , Cogan Joy , Dou Xiaoyi , Blackwell Timothy S. , Phillips John , Meiler Jens , Bush William S. , Capra John A. 
Published: February 2017

AbstractThe spatial distribution of genetic variation within proteins is shaped by evolutionary constraint and thus can provide insights into the functional importance of protein regions and the potential pathogenicity of protein alterations. Here, we comprehensively evaluate the 3D spatial patterns of constraint on human germline and somatic variation in 4,568 solved protein structures. Different classes of coding variants have significantly different spatial distributions. Neutral missense variants exhibit a range of 3D constraint patterns, with a general trend of spatial dispersion driven by constraint on core residues. In contrast, germline and somatic disease-causing variants are significantly more likely to be clustered in protein structure space. We demonstrate that this difference in the spatial distributions of disease-associated and benign germline variants provides a signature for accurately classifying variants of unknown significance (VUS) that is complementary to current approaches for VUS classification. We further illustrate the clinical utility of our approach by classifying new mutations identified from patients with familial idiopathic pneumonia (FIP) that segregate with disease.
Metagenomic DNA sequencing for the diagnosis of intraocular infections
Authors: Doan Thuy , Acharya Nisha R. , Pinsky Benjamin A. , Sahoo Malaya K. , Chow Eric D. , Banaei Niaz , Budvytiene Indre , Cevallos Vicky , Zhong Lina , Zhou Zhaoxia , Lietman Thomas M. , DeRisi Joseph L. 
Published: February 2017

ABSTRACTPurposeTo compare the performance of unbiased high-throughput sequencing with pathogen directed PCR using DNA isolated from archived ocular fluid, approaches that are compatible with the current sample handling practice of ophthalmologists.DesignRetrospective molecular study of banked vitreous samples.MethodsWe evaluated a metagenomic DNA sequencing-based approach (DNA-seq) using archived positive (n= 31) and negative (n=36) vitreous specimens as determined by reference pathogen-specific PCR assays (herpes simplex virus 1 and 2, cytomegalovirus, varicella-zoster virus, andToxoplasma gondii). Pathogens were identified using a rapid computational pipeline to analyze the non-host sequences obtained from DNA-seq. Clinical samples were de-identified and laboratory personnel handling the samples and interpreting the data were masked.ResultsMetagenomic DNA sequencing detected 87% of positive reference samples. In the presumed negative reference samples, DNA-seq detected an additional 6 different pathogens in 8 samples (22% of negative samples) that were either not detected or not targeted with pathogen-specific PCR assays. Infectious agents identified only with DNA-seq wereCandida dubliniensis,Klebsiella pneumoniae, human herpesvirus 6 (HHV-6), and human T-cell leukemia virus type 1 (HTLV-1). Discordant samples were independently verified in CLIA-certified laboratories. CMV sequences were compared against the antiviral mutation database and 3 of the samples were found to have mutations conferring ganciclovir resistance.ConclusionsMetagenomic DNA sequencing was highly concordant with pathogen-directed PCRs. The unbiased nature of metagenomics DNA sequencing allowed an expanded scope of pathogen detection, including bacteria, fungal species, and viruses, resolving 22% of cases that had previously escaped detection by routine pathogen-specific PCRs. The detection of drug resistance mutations highlights the potential for unbiased sequencing to provide clinically actionable information beyond pathogen species detection.
The locus coeruleus is a complex and differentiated neuromodulatory system
Authors: Totah Nelson K. , Neves Ricardo M. , Panzeri Stefano , Logothetis Nikos K. , Eschenko Oxana 
Published: February 2017

SummaryUnderstanding the forebrain neuromodulation by the noradrenergic locus coeruleus (LC) is fundamental for cognitive and systems neuroscience. The diffuse projections of individual LC neurons and presumably their synchronous spiking have long been perceived as features of the global nature of noradrenergic neuromodulation. Yet, the commonly referenced “synchrony” underlying global neuromodulation, has never been assessed in a large population, nor has it been related to projection target specificity. Here, we recorded up to 52 single units simultaneously (3164 unit pairs in total) in rat LC and characterized projections by stimulating 15 forebrain sites. Spike count correlations were low and, surprisingly, only 13% of pairwise spike trains had synchronized spontaneous discharge. Notably, even noxious sensory stimulation did not activate the entire population, only evoking synchronized responses in ~16% of units on each trial. We also identified novel infra-slow (0.01-1 Hz) fluctuations of LC unit spiking that were asynchronous across the population. A minority, synchronized possibly by gap junctions, was biased toward restricted (non-global) forebrain projection patterns. Finally, we characterized two types of LC single units differing by waveform shape, propensity for synchronization, and interactions with cortex. These cell types formed finely-structured ensembles. Our findings suggest that the LC conveys a highly complex, differentiated, and potentially target-specific neuromodulatory signal.
Intervene: a tool for intersection and visualization of multiple gene or genomic region sets
Authors: Khan Aziz , Mathelier Anthony 
Published: February 2017

AbstractBackgroundA common task for scientists relies on comparing lists of genes or genomic regions derived from high-throughput sequencing experiments. While several tools exist to intersect and visualize sets of genes, similar tools dedicated to the visualization of genomic region sets are currently limited.ResultsTo address this gap, we have developed the Intervene tool, which provides an easy and automated interface for the effective intersection and visualization of genomic region or list sets, thus facilitating their analysis and interpretation. Intervene contains three modules:vennto generate Venn diagrams of up to six sets,upsetto generate UpSet plots of multiple sets, andpairwiseto compute and visualize intersections of multiple sets as clustered heat maps. Intervene, and its interactive web ShinyApp companion, generate publication-quality figures for the interpretation of genomic region and list sets.ConclusionsIntervene and its web application companion provide an easy command line, and an interactive web interface to compute intersections of multiple genomic and list sets. They also have the capacity to plot intersections using easy-to-interpret visual approaches. Intervene is developed and designed to meet the needs of both computer scientists and biologists. The source code is freely available athttps://bitbucket.org/CBGR/intervene, with the web application available athttps://asntech.shinyapps.io/intervene.
Feedforward inhibition allows input summation to vary in recurrent cortical networks
Authors: Histed Mark H. 
Published: February 2017

AbstractBrain computations depend on how neurons transform inputs to spike outputs. Here, to understand input-output transformations in cortical networks, we recorded spiking responses from visual cortex (V1) of awake mice of either sex while pairing sensory stimuli with optogenetic perturbation of excitatory and parvalbumin-positive inhibitory neurons. We found V1 neurons’ average responses were primarily additive (linear). We used a recurrent cortical network model to determine if these data, as well as past observations of nonlinearity, could be described by a common circuit architecture. The model showed cortical input-output transformations can be changed from linear to sublinear with moderate (∼20%) strengthening of connections between inhibitory neurons, but this change depends on the presence of feedforward inhibition. Thus, feedforward inhibition, a common feature of cortical circuitry, enables networks to flexibly change their spiking responses via changes in recurrent connectivity.Significance statementBrains are made up of neural networks that process information by receiving input activity and transforming those inputs into output activity. We use optogenetic manipulations in awake mice to expose how a transformation in a cortical network depends on internal network activity. Combining numerical simulations with our observations uncovers that transformation depend critically on feedforward inhibition – the fact that inputs to the cortex often make strong connections on both excitatory and inhibitory neurons.
The skin barrier function gene SPINK5 is associated with challenge‐proven IgE‐mediated food allergy in infants
Authors: Ashley S. E. , Tan H.‐T. T. , Vuillermin P. , Dharmage S. C. , Tang M. L. K. , Koplin J. , Gurrin L. C. , Lowe A. , Lodge C. , Ponsonby A.‐L. , Molloy J. , Martin P. , Matheson M. C. , Saffery R. , Allen K. J. , Ellis J. A. , Martino D. ,   the HealthNuts team,   the Barwon Infant Study, the Melbourne Atopy Cohort study, the Peanut Allergen Threshold Study and the Probiotic and Peanut Oral ImmunoTherapy study
Published: February 2017

AbstractBackgroundA defective skin barrier is hypothesized to be an important route of sensitization to dietary antigens and may lead to food allergy in some children. Missense mutations in the serine peptidase inhibitor Kazal type 5 (SPINK5) skin barrier gene have previously been associated with allergic conditions.ObjectiveTo determine whether genetic variants in and around SPINK5 are associated with IgE‐mediated food allergy.MethodWe genotyped 71 “tag” single nucleotide polymorphisms (tag‐SNPs) within a region spanning ~263 kb including SPINK5 (~61 kb) in n=722 (n=367 food‐allergic, n=199 food‐sensitized‐tolerant and n=156 non‐food‐allergic controls) 12‐month‐old infants (discovery sample) phenotyped for food allergy with the gold standard oral food challenge. Transepidermal water loss (TEWL) measures were collected at 12 months from a subset (n=150) of these individuals. SNPs were tested for association with food allergy using the Cochran‐Mantel‐Haenszel test adjusting for ancestry strata. Association analyses were replicated in an independent sample group derived from four paediatric cohorts, total n=533 (n=203 food‐allergic, n=330 non‐food‐allergic), mean age 2.5 years, with food allergy defined by either clinical history of reactivity, 95% positive predictive value (PPV) or challenge, corrected for ancestry by principal components.ResultsSPINK5 variant rs9325071 (A⟶G) was associated with challenge‐proven food allergy in the discovery sample (P=.001, OR=2.95, CI=1.49‐5.83). This association was further supported by replication (P=.007, OR=1.58, CI=1.13‐2.20) and by meta‐analysis (P=.0004, OR=1.65). Variant rs9325071 is associated with decreased SPINK5 gene expression in the skin in publicly available genotype‐tissue expression data, and we generated preliminary evidence for association of this SNP with elevated TEWL also.ConclusionsWe report, for the first time, association between SPINK5 variant rs9325071 and challenge‐proven IgE‐mediated food allergy.
Dysregulation of metabolic pathways in a mouse model of allergic asthma
Authors: Quinn K. D. , Schedel M. , Nkrumah‐Elie Y. , Joetham A. , Armstrong M. , Cruickshank‐Quinn C. , Reisdorph R. , Gelfand E. W. , Reisdorph N. 
Published: February 2017

AbstractBackgroundAsthma is a complex lung disease resulting from the interplay of genetic and environmental factors. To understand the molecular changes that occur during the development of allergic asthma without genetic and environmental confounders, an experimental model of allergic asthma in mice was used. Our goals were to (1) identify changes at the small molecule level due to allergen exposure, (2) determine perturbed pathways due to disease, and (3) determine whether small molecule changes correlate with lung function.MethodsIn this experimental model of allergic asthma, matched bronchoalveolar lavage (BAL) fluid and plasma were collected from three groups of C57BL6 mice (control vs sensitized and/or challenged with ovalbumin, n=3‐5/group) 6 hour, 24 hour, and 48 hour after the last challenge. Samples were analyzed using liquid chromatography‐mass spectrometry‐based metabolomics. Airway hyper‐responsiveness (AHR) measurements and differential cell counts were performed.ResultsIn total, 398 and 368 dysregulated metabolites in the BAL fluid and plasma of sensitized and challenged mice were identified, respectively. These belonged to four, interconnected pathways relevant to asthma pathogenesis: sphingolipid metabolism (P=6.6×10−5), arginine and proline metabolism (P=1.12×10−7), glycerophospholipid metabolism (P=1.3×10−10), and the neurotrophin signaling pathway (P=7.0×10−6). Furthermore, within the arginine and proline metabolism pathway, a positive correlation between urea‐1‐carboxylate and AHR was observed in plasma metabolites, while ornithine revealed a reciprocal effect. In addition, agmatine positively correlated with lung eosinophilia.ConclusionThese findings point to potential targets and pathways that may be central to asthma pathogenesis and can serve as novel therapeutic targets.
Transfusion in critical care – a UK regional audit of current practice
Authors: Plumb J. O. M. , Taylor M. G. , Clissold E. , Grocott M. P. W. , Gill R. ,   the South Coast Peri‐operative Audit and Research Collaboration (SPARC)
Published: February 2017

SummaryA consistent message within critical care publications has been that a restrictive transfusion strategy is non‐inferior, and possibly superior, to a liberal strategy for stable, non‐bleeding critically ill patients. Translation into clinical practice has, however, been slow. Here, we describe the degree of adherence to UK best practice guidelines in a regional network of nine intensive care units within Wessex. All transfusions given during a 2‐month period were included (n = 444). Those given for active bleeding or within 24 h of major surgery, trauma or gastrointestinal bleeding were excluded (n = 148). The median (IQR [range]) haemoglobin concentration before transfusion was 73 (68–77 [53–106]) g.l−1, with only 34% of transfusion episodes using a transfusion threshold of < 70 g.l−1. In a subgroup analysis that did not study patients with a history of cardiac disease (n = 42), haemoglobin concentration before transfusion was 72 (68–77 [50–98]) g.l−1, with only 36% of transfusion episodes using a threshold of < 70 g.l−1 (see Fig. 3). Most blood transfusions given to critically ill patients who were not bleeding in this audit used a haemoglobin threshold > 70 g.l−1. The reason why recommendations on transfusion triggers have not translated into clinical practice is unclear. With a clear national drive to decrease usage of blood products and clear evidence that a threshold of 70 g.l−1 is non‐inferior, it is surprising that a scarce and potentially dangerous resource is still being overused within critical care. Simple solutions such as electronic patient records that force pause for thought before blood transfusion, or prescriptions that only allow administration of a single unit in non‐emergency circumstances may help to reduce the incidence of unnecessary blood transfusions.
Novel method to assess intrinsic heart rate recovery in ambulatory ECG recordings tracks cardioprotective effects of chronic autonomic regulation therapy in patients enrolled in the ANTHEM‐HF study
Authors: Carlson Gerrard M. , Libbus Imad , Amurthur Badri , KenKnight Bruce H. , Verrier Richard L. 
Published: February 2017

BackgroundPostexercise heart rate recovery (HRR) is a powerful and independent predictor of mortality. Autonomic regulation therapy (ART) with chronic vagus nerve stimulation (VNS) has been shown to improve ventricular function in patients with chronic heart failure. However, the effect of ART on HRR in patients with heart failure remains unknown.MethodsA new measure involving quantification of intrinsic HRR was developed for 24‐hr ambulatory ECG (AECG) recordings based on spontaneous heart rate changes observed during daily activity in patients with symptomatic heart failure and reduced ejection fraction. Intrinsic HRR values were compared in 21 patients enrolled in the ANTHEM‐HF study (NCT01823887) before and after 12 months of chronic ART (10 Hz, 250 μs pulse width, 18% duty cycle, maximum tolerable current amplitude after 10 weeks of titration) and to values from normal subjects (PhysioNet database, n = 54).ResultsWith chronic ART, average intrinsic HRR was improved as indicated by a shortening of the rate‐recovery time constant by 8.9% (from 12.3 ± 0.1 at baseline to 11.2 ± 0.1 s, p < .0001) among patients receiving high‐intensity stimuli (≥2 mA). In addition, mean heart rate decreased by 8.5 bpm (from 75.9 ± 2.6 to 67.4 ± 2.9 bpm, p = .005) and left ventricular ejection fraction (LVEF) increased by 4.7% (from 32.6 ± 2.0% to 37.3 ± 1.9%, p < .005).ConclusionUsing a new technique adapted for 24‐hr AECG recordings, intrinsic HRR was found to be impaired in patients with symptomatic HF compared to normal subjects. Chronic ART significantly improved intrinsic HRR, indicating an improvement in autonomic function.
Diagnostic accuracy of Charcot's triad: a systematic review
Authors: Rumsey Steva , Winders Joel , MacCormick Andrew D. 
Published: February 2017

BackgroundCharcot's triad is a well‐established diagnostic tool for acute cholangitis (AC). It has been recognized as an inaccurate test in clinical practice; however, its exact sensitivity and specificity remain unclear. This knowledge is key to informing the value of its continued clinical application. The objectives of this study are to calculate an estimate of the sensitivity and specificity of Charcot's triad based on published research and consider its applicability to clinical practice and medical education.MethodsElectronic database search for relevant literature and review of reference lists of the subsequent articles for additional resources. Two independent researchers located articles which were qualitatively and quantitatively reviewed. The overall sensitivity and specificity values across all studies were subsequently calculated.ResultsThe 16 articles included in the review varied widely in study design and the sensitivity of Charcot's triad was reported for AC. Across the included articles, there were 4288 patients studied. The overall sensitivity for Charcot's triad was calculated as 36.3%. The specificity was only analysed in three studies and had an overall value of 93.2%. Nine of the articles also investigated the sensitivity of Reynold's pentad which was consistently low with an overall value of 4.82%. The specificity of Reynold's pentad was not studied.ConclusionCharcot's triad has limited clinical utility as a diagnostic algorithm for AC. It is an effective rule‐in test but a poor rule‐out test and should be applied and taught accordingly. A more sensitive diagnostic tool is required to achieve superior outcomes for AC patients.