bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ultra–Low-Dose Ultrasound Molecular Imaging for the Detection of Angiogenesis in a Mouse Murine Tumor Model
Authors: Wang Shiying , Herbst Elizabeth B. , Mauldin F. William , Diakova Galina B. , Klibanov Alexander L. , Hossack John A. 
Published: September 2016

Objectives
The objective of this study was to evaluate the minimum microbubble dose for ultrasound molecular imaging to achieve statistically significant detection of angiogenesis in a mouse model.

Materials and Methods
The preburst minus postburst method was implemented on a Verasonics ultrasound research scanner using a multiframe compounding pulse inversion imaging sequence. Biotinylated lipid (distearoyl phosphatidylcholine–based) microbubbles that were conjugated with antivascular endothelial growth factor 2 (VEGFR2) antibody (MBVEGFR2) or isotype control antibody (MBControl) were injected into mice carrying adenocarcinoma xenografts. Different injection doses ranging from 5 × 104 to 1 × 107 microbubbles per mouse were evaluated to determine the minimum diagnostically effective dose.

Results
The proposed imaging sequence was able to achieve statistically significant detection (P < 0.05, n = 5) of VEGFR2 in tumors with a minimum MBVEGFR2 injection dose of only 5 × 104 microbubbles per mouse (distearoyl phosphatidylcholine at 0.053 ng/g mouse body mass). Nonspecific adhesion of MBControl at the same injection dose was negligible. In addition, the targeted contrast ultrasound signal of MBVEGFR2 decreased with lower microbubble doses, whereas nonspecific adhesion of MBControl increased with higher microbubble doses.

Conclusions
The dose of 5 × 104 microbubbles per animal is now the lowest injection dose on record for ultrasound molecular imaging to achieve statistically significant detection of molecular targets in vivo. Findings in this study provide us with further guidance for future developments of clinically translatable ultrasound molecular imaging applications using a lower dose of microbubbles.
Simultaneous Multislice Diffusion-Weighted Imaging of the Kidney
Authors: Kenkel David , Barth Borna K. , Piccirelli Marco , Filli Lukas , Finkenstädt Tim , Reiner Cäcilia S. , Boss Andreas 
Published: September 2016

Objectives
The aims of this study were to implement a protocol for simultaneous multislice (SMS) accelerated diffusion-weighted imaging (DWI) of the kidneys and to perform a systematic analysis of image quality of the data sets.

Materials and Methods
Ten healthy subjects and 5 patients with renal masses underwent DWI of the kidney in this prospective institutional review board–approved study on a 3 T magnetic resonance scanner. Simultaneous multislice DWI echo-planar sequences (acceleration factors [AFs] 2 and 3) were compared with conventional echo-planar DWI as reference standard for each acquisition scheme. The following 3 acquisition schemes were applied: comparison A, with increased number of acquisitions at constant scan time; comparison B, with reduction of acquisition time; and comparison C, with increased slice resolution (constant acquisition time, increasing number of slices). Interreader reliability was analyzed by calculating the intraclass correlation coefficient (ICC). Qualitative image quality features were evaluated by 2 independent radiologists on a 5-point Likert scale. Quantification accuracy of the apparent diffusion coefficients (ADCs) and signal-to-noise ratios (SNRs) were assessed by region of interest analysis. Furthermore, lesion conspicuity in the 5 patients was assessed using a 5-point Likert scale by 2 independent radiologists.

Results
Interreader agreement was substantial with an ICC of 0.68 for the overall image quality and an ICC of 0.73 for the analysis of artifacts. In comparison A, AF2 resulted in increased SNR (P < 0.05) by 21% at stable image quality scores (image quality: P = 0.76, artifacts: P = 0.21). In comparison B, applying AF2, the scan time could be reduced by 46% without significant reduction in qualitative image quality scores (P = 0.059) or SNR (P = 0.126). In comparison C, slice resolution could be improved by 28% using AF2 with stable image quality scores and SNR. In general, AF3 resulted in reduced image quality and SNR. Significantly reduced ADC values were observed for AF3 in comparison C (cortex: P = 0.003; medulla: P = 0.001) compared with the standard echo-planar imaging sequence. The conventional DWI and the SMS DWI with AF2 showed stable lesion conspicuity ([AF1/AF2]: reader 1 [1.8/1.4] and reader 2 [1.8/1.4]). The lesion conspicuity was lower using AF3 (reader 1: 2.2 and reader 2: 1.8).

Conclusions
In conclusion, SMS DWI of the kidney is a potential tool to substantially reduce scan time without negative effects on SNR, ADC quantification accuracy, and image quality if an AF2 is used. Although AF3 results in even higher scan time reduction, a negative impact on image quality, SNR, ADC quantification accuracy, and lesion conspicuity must be considered.
Gut microbiota, 1013 new pieces in the Parkinson's disease puzzle
Authors: Scheperjans Filip 
Published: September 2016

Purpose of review
Gastrointestinal dysfunction is highly prevalent in Parkinson's disease and may precede motor symptoms by more than a decade. It has been proposed that the neurodegenerative cascade may actually be initiated in the gut with subsequent spreading to the brain and that gut microbiota could be involved in this process. This review provides a short introduction into the methodology of microbiome-wide association studies and discusses the recently published first comprehensive assessments of gut microbiota in Parkinson's disease.

Recent findings
Three case–control studies have studied gut microbiota composition in Parkinson's disease and all found significant differences between Parkinson's disease patients and controls. However, most of the differentially abundant taxa as well as associations of microbiota with clinical variables differed between studies. This may at least in part be explained by methodological differences between studies in terms of selection of participants, analysis pipelines, statistical analysis, and confounder control.

Summary
Current evidence suggests that there are alterations of gut microbiota in Parkinson's disease, but the exact nature of these changes is not established. Future larger studies should assess gut microbiota in Parkinson's disease covering diverse geographical regions, ethnicities, disease stages, and phenotypes using well-defined selection criteria for patients and controls and standardized methodology.
Neurologic complications of immune checkpoint inhibitors
Authors: Hottinger Andreas F. 
Published: September 2016

Purpose of review
In recent years, advances in the understanding of the regulatory mechanisms of the immune system has led to the development of new approaches for cancer treatment. Currently, immune checkpoint inhibitors are the first successful examples of this approach and several agents that target cytotoxic lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-1 (PD-1) have been approved for various oncologic situations. The aim of this review is to describe the neurologic adverse event profiles for these new immune therapeutic approaches and to discuss their appropriate management.

Recent findings
The immune checkpoint inhibitor ipilimumab against CTLA-4 and nivolumab or pembrolizumab against PD-1 show a unique spectrum of toxic effects. The most common toxicities include rash, colitis, hepatitis, endocrinopathies, and pneumonitis. Neurologic side-effects are rare but include cases of immune polyneuropathies, Guillain Barré syndrome, myasthenia gravis, posterior reversible encephalopathy syndrome, aseptic meningitis, enteric neuropathy, transverse myelitis as well as immune encephalitis.

Summary
It is essential that neurologic immune-related adverse events are recognized and treated as soon as possible, as early treatment increases the odds of a complete recovery.
Stable isotope dimethyl labelling for quantitative proteomics and beyond
Authors: Hsu Jue-Liang , Chen Shu-Hui 
Published: September 2016

Stable-isotope reductive dimethylation, a cost-effective, simple, robust, reliable and easy-to- multiplex labelling method, is widely applied to quantitative proteomics using liquid chromatography-mass spectrometry. This review focuses on biological applications of stable-isotope dimethyl labelling for a large-scale comparative analysis of protein expression and post-translational modifications based on its unique properties of the labelling chemistry. Some other applications of the labelling method for sample preparation and mass spectrometry-based protein identification and characterization are also summarized.
This article is part of the themed issue ‘Quantitative mass spectrometry’.
Good quantification practices of flavours and fragrances by mass spectrometry
Authors: Begnaud Frédéric , Chaintreau Alain 
Published: September 2016

Over the past 15 years, chromatographic techniques with mass spectrometric detection have been increasingly used to monitor the rapidly expanded list of regulated flavour and fragrance ingredients. This trend entails a need for good quantification practices suitable for complex media, especially for multi-analytes. In this article, we present experimental precautions needed to perform the analyses and ways to process the data according to the most recent approaches. This notably includes the identification of analytes during their quantification and method validation, when applied to real matrices, based on accuracy profiles. A brief survey of application studies based on such practices is given.This article is part of the themed issue ‘Quantitative mass spectrometry’.
Quantitative proteomics and terminomics to elucidate the role of ubiquitination and proteolysis in adaptive immunity
Authors: Klein Theo , Viner Rosa I. , Overall Christopher M. 
Published: September 2016

Adaptive immunity is the specialized defence mechanism in vertebrates that evolved to eliminate pathogens. Specialized lymphocytes recognize specific protein epitopes through antigen receptors to mount potent immune responses, many of which are initiated by nuclear factor-kappa B activation and gene transcription. Most, if not all, pathways in adaptive immunity are further regulated by post-translational modification (PTM) of signalling proteins, e.g. phosphorylation, citrullination, ubiquitination and proteolytic processing. The importance of PTMs is reflected by genetic or acquired defects in these pathways that lead to a dysfunctional immune response. Here we discuss the state of the art in targeted proteomics and systems biology approaches to dissect the PTM landscape specifically regarding ubiquitination and proteolysis in B- and T-cell activation. Recent advances have occurred in methods for specific enrichment and targeted quantitation. Together with improved instrument sensitivity, these advances enable the accurate analysis of often rare PTM events that are opaque to conventional proteomics approaches, now rendering in-depth analysis and pathway dissection possible. We discuss published approaches, including as a case study the profiling of the N-terminome of lymphocytes of a rare patient with a genetic defect in the paracaspase protease MALT1, a key regulator protease in antigen-driven signalling, which was manifested by elevated linear ubiquitination.
This article is part of the themed issue ‘Quantitative mass spectrometry’.
Revisiting the quantitative features of surface-assisted laser desorption/ionization mass spectrometric analysis
Authors: Wu Ching-Yi , Lee Kai-Chieh , Kuo Yen-Ling , Chen Yu-Chie 
Published: September 2016

Surface-assisted laser desorption/ionization (SALDI) coupled with mass spectrometry (MS) is frequently used to analyse small organics owing to its clean background. Inorganic materials can be used as energy absorbers and the transfer medium to facilitate the desorption/ionization of analytes; thus, they are used as SALDI-assisting materials. Many studies have demonstrated the usefulness of SALDI-MS in quantitative analysis of small organics. However, some characteristics occurring in SALDI-MS require certain attention to ensure the reliability of the quantitative analysis results. The appearance of a coffee-ring effect in SALDI sample preparation is the primary factor that can affect quantitative SALDI-MS analysis results. However, to the best of our knowledge, there are no reports relating to quantitative SALDI-MS analysis that discuss or consider this effect. In this study, the coffee-ring effect is discussed using nanoparticles and nanostructured substrates as SALDI-assisting materials to show how this effect influences SALDI-MS analysis results. Potential solutions for overcoming the existing problems are also suggested.
This article is part of the themed issue ‘Quantitative mass spectrometry’.
Quantitative mass spectrometry of unconventional human biological matrices
Authors: Dutkiewicz Ewelina P. , Urban Pawel L. 
Published: September 2016

The development of sensitive and versatile mass spectrometric methodology has fuelled interest in the analysis of metabolites and drugs in unconventional biological specimens. Here, we discuss the analysis of eight human matrices—hair, nail, breath, saliva, tears, meibum, nasal mucus and skin excretions (including sweat)—by mass spectrometry (MS). The use of such specimens brings a number of advantages, the most important being non-invasive sampling, the limited risk of adulteration and the ability to obtain information that complements blood and urine tests. The most often studied matrices are hair, breath and saliva. This review primarily focuses on endogenous (e.g. potential biomarkers, hormones) and exogenous (e.g. drugs, environmental contaminants) small molecules. The majority of analytical methods used chromatographic separation prior to MS; however, such a hyphenated methodology greatly limits analytical throughput. On the other hand, the mass spectrometric methods that exclude chromatographic separation are fast but suffer from matrix interferences. To enable development of quantitative assays for unconventional matrices, it is desirable to standardize the protocols for the analysis of each specimen and create appropriate certified reference materials. Overcoming these challenges will make analysis of unconventional human biological matrices more common in a clinical setting.This article is part of the themed issue ‘Quantitative mass spectrometry’.
Quantitative mass spectrometry: an overview
Authors: Urban Pawel L. 
Published: September 2016

Mass spectrometry (MS) is a mainstream chemical analysis technique in the twenty-first century. It has contributed to numerous discoveries in chemistry, physics and biochemistry. Hundreds of research laboratories scattered all over the world use MS every day to investigate fundamental phenomena on the molecular level. MS is also widely used by industry—especially in drug discovery, quality control and food safety protocols. In some cases, mass spectrometers are indispensable and irreplaceable by any other metrological tools. The uniqueness of MS is due to the fact that it enables direct identification of molecules based on the mass-to-charge ratios as well as fragmentation patterns. Thus, for several decades now, MS has been used in qualitative chemical analysis. To address the pressing need for quantitative molecular measurements, a number of laboratories focused on technological and methodological improvements that could render MS a fully quantitative metrological platform. In this theme issue, the experts working for some of those laboratories share their knowledge and enthusiasm about quantitative MS. I hope this theme issue will benefit readers, and foster fundamental and applied research based on quantitative MS measurements.
This article is part of the themed issue ‘Quantitative mass spectrometry’.
Dynamic Brain Connectivity Patterns in Conscious and Unconscious Brain
Authors: Ma Yuncong , Hamilton Christina , Zhang Nanyin 
Published: September 2016

AbstractBrain functional connectivity undergoes dynamic changes from the awake to unconscious states. However, how the dynamics of functional connectivity patterns are linked to consciousness at the behavioral level remains elusive. Here we acquired resting-state functional magnetic resonance imaging (rsfMRI) data during wakefulness and graded levels of consciousness in rats. Data were analyzed using a dynamic approach combining the sliding-window method and k-means clustering. Our results demonstrate that whole-brain networks contain several quasi-stable patterns that dynamically recurred from the awake state into anesthetized states. Remarkably, two brain connectivity states with distinct spatial similarity to the structure of anatomical connectivity were strongly biased toward high and low consciousness levels, respectively. These results provide compelling neuroimaging evidence linking the dynamics of whole-brain functional connectivity patterns and states of consciousness at the behavioral level.Conflict of interestnone.
Mapping eQTLs With RNA-Seq Reveals Novel SLE Susceptibility Genes, Non-Coding RNAs, and Alternative-Splicing Events That Are Concealed Using Microarrays
Authors: Odhams Christopher A. , Cortini Andrea , Chen Lingyan , Roberts Amy L. , Vinuela Ana , Buil Alfonso , Small Kerrin S. , Dermitzakis Emmanouil T. , Morris David L. , Vyse Timothy J. , Cunninghame Graham Deborah S. 
Published: September 2016

AbstractStudies attempting to functionally interpret complex-disease susceptibility loci by GWAS and eQTL integration have predominantly employed microarrays to quantify gene-expression. RNA-Seq has the potential to discover a more comprehensive set of eQTLs and illuminate the underlying molecular consequence. We examine the functional outcome of 39 variants associated with Systemic Lupus Erythematosus (SLE) through integration of GWAS and eQTL data from the TwinsUK microarray and RNA-Seq cohort in lymphoblastoid cell lines. We use conditional analysis and a Bayesian colocalisation method to provide evidence of a shared causal-variant, then compare the ability of each quantification type to detect disease relevant eQTLs and eGenes. We discovered a greater frequency of candidate-causal eQTLs using RNA-Seq, and identified novel SLE susceptibility genes that were concealed using microarrays (e.g.NADSYN1,SKP1, andTCF7). Many of these eQTLs were found to influence the expression of several genes, suggesting risk haplotypes may harbour multiple functional effects. We pinpointed eQTLs modulating expression of four non-coding RNAs; three of which were replicated in whole-blood. Novel SLE associated splicing events were identified in the T-reg restricted transcription factor,IKZF2, the autophagy-related geneWDFY4, and the redox coenzymeNADSYN1, through asQTL mapping using the Geuvadis cohort. We have significantly increased our understanding of the genetic control of gene-expression in SLE by maximising the leverage of RNA-Seq and performing integrative GWAS-eQTL analysis against gene, exon, and splice-junction quantifications. In doing so, we have identified novel SLE candidate genes and specific molecular mechanisms that will serve as the basis for targeted follow-up studies.
De novotranscriptome assembly for the spiny mouse (Acomys cahirinus)
Authors: Mamrot Jared , Legaie Roxane , Ellery Stacey J , Wilson Trevor , Gardner David K. , Walker David W. , Temple-Smith Peter , Papenfuss Anthony T. , Dickinson Hayley 
Published: September 2016

AbstractBackground: Spiny mice of the genusAcomysare small desert-dwelling rodents that display physiological characteristics not typically found in rodents. Recent investigations have reported a menstrual cycle and scar free-wound healing in this species; characteristics that are exceedingly rare in mammals, and of considerable interest to the scientific community. These unique physiological traits, and the potential for spiny mice to accurately model human diseases, are driving increased use of this genus in biomedical research. However, little genetic information is currently available forAcomys, limiting the application of some modern investigative techniques. This project aimed to generate a reference transcriptome assembly for the common spiny mouse (Acomys cahirinus).Results: Illumina RNA sequencing of male and female spiny mice produced 451 million, 150bp paired-end reads from 15 organ types. An extensive survey ofde novotranscriptome assembly approaches of high-quality reads using Trinity, SOAPdenovo-Trans, and Velvet/Oases at multiple kmer lengths was conducted with 49 single-kmer assemblies generated from this dataset, with and withoutin siliconormalization and probabilistic error correction. Merging transcripts from 49 individual single-kmer assemblies into a single meta-assembly of non-redundant transcripts using the EvidentialGene ‘tr2aacds’ pipeline produced the highest quality transcriptome assembly, comprised of 880,080 contigs, of which 189,925 transcripts were annotated using the SwissProt/Uniprot database.Conclusions: This study provides the first detailed characterization of the spiny mouse transcriptome. It validates the application of the EvidentialGene ‘tr2aacds’ pipeline to generate a high-quality reference transcriptome assembly in a mammalian species, and provides a valuable scientific resource for further investigation into the unique physiological characteristics inherent in the genusAcomys.
High throughput estimation of functional cell activities reveals disease mechanisms and predicts relevant clinical outcomes
Authors: Hidalgo Marta R. , Cubuk Cankut , Amadoz Alicia , Salavert Francisco , Carbonell-Caballero José , Dopazo Joaquin 
Published: September 2016

AbstractUnderstanding the aspects of the cell functionality that account for disease or drug action mechanisms is a main challenge for precision medicine. Here we propose a new method that models cell signaling using biological knowledge on signal transduction. The method recodes individual gene expression values (and/or gene mutations) into accurate measurements of changes in the activity of signaling circuits, which ultimately constitute high-throughput estimations of cell functionalities caused by gene activity within the pathway. Moreover, such estimations can be obtained either at cohort-level, in case/control comparisons, or personalized for individual patients. The accuracy of the method is demonstrated in an extensive analysis involving 5640 patients from 12 different cancer types. Circuit activity measurements not only have a high diagnostic value but also can be related to relevant disease outcomes such as survival, and can be used to assess therapeutic interventions.