bluuebunny/crossref_metadata_2025 huggingface dataset:
What has single-cell RNA-seq taught us about mammalian spermatogenesis?
Authors: Suzuki Shinnosuke , Diaz Victoria D , Hermann Brian P
Published: May 2019

Mammalian spermatogenesis is a complex developmental program that transforms mitotic testicular germ cells (spermatogonia) into mature male gametes (sperm) for production of offspring. For decades, it has been known that this several-weeks-long process involves a series of highly ordered and morphologically recognizable cellular changes as spermatogonia proliferate, spermatocytes undertake meiosis, and spermatids develop condensed nuclei, acrosomes, and flagella. Yet, much of the underlying molecular logic driving these processes has remained opaque because conventional characterization strategies often aggregated groups of cells to meet technical requirements or due to limited capability for cell selection. Recently, a cornucopia of single-cell transcriptome studies has begun to lift the veil on the full compendium of gene expression phenotypes and changes underlying spermatogenic development. These datasets have revealed the previously obscured molecular heterogeneity among and between varied spermatogenic cell types and are reinvigorating investigation of testicular biology. This review describes the extent of available single-cell RNA-seq profiles of spermatogenic and testicular somatic cells, how those data were produced and evaluated, their present value for advancing knowledge of spermatogenesis, and their potential future utility at both the benchtop and bedside.
Why only humans and social insects have a division of labour
Authors: Pagano Ugo
Published: May 2019

Humans and social insects are located at extreme points of the set of possible evolutionary paths. However, they share a complex division of labour and comprise a large proportion of the earth’s biomass. These observations prompt two questions: If there are evident evolutionary advantages of cooperation and specialisation, why have only few species been able to increase their fitness in this way? Why have these characteristics emerged as such extremely different forms of life? In order to answer these two questions, we will focus on possible ‘transition societies’ in the evolutionary paths towards social species. We will argue that, in both the human and social insect cases, sexual selection had a crucial role in the development of the division of labour and entailed that the division of labour required either minimum or maximum unitary investments in the offspring. The species located in between these two extremes could not exploit the advantages of specialisation.
Toward a Sign Language-Friendly Questionnaire Design
Authors: Bosch-Baliarda Marta , Soler Vilageliu Olga , Orero Pilar
Published: May 2019

The United Nations Convention on the Rights of Persons with Disabilities requests “Nothing about us without us.” User-centered methodological research is the way to comply with this convention. Interaction with the deaf community must be in their language; hence sign language questionnaires are one of the tools to gather data. While in the past interacting with an online video questionnaire was out of the question, today it is a reality. This article focuses on the design of an interactive video questionnaire for sign language users. From a historical review of the existing literature on research methods and previous sign language questionnaire, the article examines the design features affected in the process of making accessible questionnaires with sign language videos: format and layout. The article finishes with the solution developed toward mainstreaming sign language questionnaires in order to contribute to a diverse and inclusive society for all citizens.
Disparities in esophageal cancer: less treatment, less surgical resection, and poorer survival in disadvantaged patients
Authors: Schlottmann Francisco , Gaber Charles , Strassle Paula D , Herbella Fernando A M , Molena Daniela , Patti Marco G
Published: May 2019

The incidence of esophageal cancer has increased steadily in the last decades in the United States. The aim of this paper was to characterize disparities in esophageal cancer treatment in different racial and socioeconomic population groups and compare long-term survival among different treatment modalities. A retrospective analysis of the National Cancer Database was performed including adult patients (≥18 years old) with a diagnosis of resectable (stages I–III) esophageal cancer between 2004 and 2015. Multivariable logistic regression models were used to determine the odds of being offered no treatment at all and surgical treatment across race, primary insurance, travel distance, income, and education levels. Multivariable Cox proportional hazards models were used to compare 5-year survival rates across different treatment modalities. A total of 60,621 esophageal cancer patients were included. Black patients, uninsured patients, and patients living in areas with lower levels of education were more likely to be offered no treatment. Similarly, black race, female patients, nonprivately insured patients, and those living in areas with lower median residential income and lower education levels were associated with lower rates of surgery. Patients receiving surgical treatment, compared to both no treatment and definitive chemoradiation, had significant better long-term survival in stage I, II, and III esophageal cancer. In conclusion, underserved patients with esophageal cancer appear to have limited access to surgical care, and are, in fact, more likely to not be offered any treatment at all. Considering the survival benefits associated with surgical resection, greater public health efforts to reduce disparities in esophageal cancer are needed.
Management of cardiogenic shock complicating myocardial infarction: an update 2019
Authors: Thiele Holger , Ohman E Magnus , de Waha-Thiele Suzanne , Zeymer Uwe , Desch Steffen
Published: May 2019

Cardiogenic shock (CS) remains the most common cause of death in patients admitted with acute myocardial infarction (AMI) and mortality remained nearly unchanged in the range of 40–50% during the last two decades. Early revascularization, vasopressors and inotropes, fluids, mechanical circulatory support, and general intensive care measures are widely used for CS management. However, there is only limited evidence for any of the above treatment strategies except for revascularization and the relative ineffectiveness of intra-aortic balloon pumping. This updated review will outline the management of CS complicating AMI with major focus on state-of-the art treatment.
De novo transcriptome assembly: A comprehensive cross-species comparison of short-read RNA-Seq assemblers
Authors: Hölzer Martin , Marz Manja
Published: May 2019

Background

In recent years, massively parallel complementary DNA sequencing (RNA sequencing [RNA-Seq]) has emerged as a fast, cost-effective, and robust technology to study entire transcriptomes in various manners. In particular, for non-model organisms and in the absence of an appropriate reference genome, RNA-Seq is used to reconstruct the transcriptome de novo. Although the de novo transcriptome assembly of non-model organisms has been on the rise recently and new tools are frequently developing, there is still a knowledge gap about which assembly software should be used to build a comprehensive de novo assembly.

Results

Here, we present a large-scale comparative study in which 10 de novo assembly tools are applied to 9 RNA-Seq data sets spanning different kingdoms of life. Overall, we built >200 single assemblies and evaluated their performance on a combination of 20 biological-based and reference-free metrics. Our study is accompanied by a comprehensive and extensible Electronic Supplement that summarizes all data sets, assembly execution instructions, and evaluation results. Trinity, SPAdes, and Trans-ABySS, followed by Bridger and SOAPdenovo-Trans, generally outperformed the other tools compared. Moreover, we observed species-specific differences in the performance of each assembler. No tool delivered the best results for all data sets.

Conclusions

We recommend a careful choice and normalization of evaluation metrics to select the best assembling results as a critical step in the reconstruction of a comprehensive de novo transcriptome assembly.
A highly predictive signature of cognition and brain atrophy for progression to Alzheimer's dementia
Authors: Tam Angela , Dansereau Christian , Iturria-Medina Yasser , Urchs Sebastian , Orban Pierre , Sharmarke Hanad , Breitner John , Bellec Pierre ,   Alzheimer's Disease Neuroimaging Initiative
Published: May 2019

Background

Clinical trials in Alzheimer's disease need to enroll patients whose cognition will decline over time, if left untreated, in order to demonstrate the efficacy of an intervention. Machine learning models used to screen for patients at risk of progression to dementia should therefore favor specificity (detecting only progressors) over sensitivity (detecting all progressors), especially when the prevalence of progressors is low. Here, we explore whether such high-risk patients can be identified using cognitive assessments and structural neuroimaging by training machine learning tools in a high-specificity regime.

Results

A multimodal signature of Alzheimer's dementia was first extracted from the ADNI1 dataset. We then validated the predictive value of this signature on ADNI1 patients with mild cognitive impairment (N = 235). The signature was optimized to predict progression to dementia over 3 years with low sensitivity (55.1%) but high specificity (95.6%), resulting in only moderate accuracy (69.3%) but high positive predictive value (80.4%, adjusted for a “typical” 33% prevalence rate of true progressors). These results were replicated in ADNI2 (N = 235), with 87.8% adjusted positive predictive value (96.7% specificity, 47.3% sensitivity, 85.1% accuracy).

Conclusions

We found that cognitive measures alone could identify high-risk individuals, with structural measurements providing a slight improvement. The signature had comparable receiver operating characteristics to standard machine learning tools, yet a marked improvement in positive predictive value was achieved over the literature by selecting a high-specificity operating point. The multimodal signature can be readily applied for the enrichment of clinical trials.
How altering the modular architecture affects aspects of lectin activity: case study on human galectin-1
Authors: Kutzner Tanja J , Gabba Adele , FitzGerald Forrest G , Shilova Nadezhda V , García Caballero Gabriel , Ludwig Anna-Kristin , Manning Joachim C , Knospe Clemens , Kaltner Herbert , Sinowatz Fred , Murphy Paul V , Cudic Mare , Bovin Nicolai V , Gabius Hans-Joachim
Published: May 2019

Discoveries on involvement of glycan–protein recognition in many (patho)physiological processes are directing attention to exploring the significance of a fundamental structural aspect of sugar receptors beyond glycan specificity, i.e., occurrence of distinct types of modular architecture. In order to trace clues for defining design–functionality relationships in human lectins, a lectin's structural unit has been used as source material for engineering custom-made variants of the wild-type protein. Their availability facilitates comparative analysis toward the stated aim. With adhesion/growth-regulatory human galectin-1 as example, the strategy of evaluating how changes of its design (here, from the homodimer of non-covalently associated domains to (i) linker-connected di- and tetramers and (ii) a galectin-3-like protein) affect activity is illustrated by using three assay systems of increasing degree of glycan complexity. Whereas calorimetry with two cognate disaccharides and array testing with 647 (glyco)compounds disclosed no major changes, galectin histochemical staining profiles of tissue sections that present natural glycome complexity revealed differences between wild-type and linker-connected homo-oligomers as well as between the galectin-3-like variant and wild-type galectin-3 for cell-type positivity, level of intensity at the same site and susceptibility for inhibition by a bivalent glycocompound. These results underscore the strength of the documented approach. Moreover, they give direction to proceed to (i) extending its application to other members of this lectin family, especially galectin-3 and (ii) then analyzing impact of architectural alterations on cell surface lattice formation and ensuing biosignaling systematically, considering the variants’ potential for translational medicine.
Presence of NDM in non-E. coli Enterobacteriaceae in the poultry production environment
Authors: Zhang Rongmin , Li Jiyun , Wang Yang , Shen Jianzhong , Shen Zhangqi , Wang Shaolin
Published: May 2019

Objectives

Characterization of non-Escherichia coli NDM-carrying Enterobacteriaceae in the poultry production environment.

Methods

A total of 36 NDM-positive Enterobacteriaceae (22 Klebsiella pneumoniae, 13 Enterobacter cloacae and 1 Salmonella enterica) were isolated from a chicken farm and WGS was conducted using Illumina Hiseq2500. The genomic characterization of the isolates acquired through WGS analysis included the genomic context-flanking blaNDM genes, MLST, the antibiotic resistance genes (ARGs) and replicon types of plasmids. WGS information for another 73 K. pneumoniae isolates from different sources was retrieved from GenBank and then combined with isolates in this study for comparative genomic and phylogenetic analysis.

Results

Three types of genetic environment carrying blaNDM were identified in 36 non-E. coli Enterobacteriaceae isolates. Sequence comparison analysis indicated these genetic environments were completely identical to our previous findings. WGS further revealed three major types of plasmids (IncFIB, IncX3 and IncFII) from these isolates and the phylogenetic analysis suggested several K. pneumoniae isolates with ST11, ST37 and ST147 from the commercial chicken farm that were closely related to isolates of human origin.

Conclusions

The blaNDM-harbouring genetic contexts were identified not only in E. coli, but also in K. pneumoniae, E. cloacae and S. enterica, which may indicate that blaNDM has been widely disseminated to non-E. coli Enterobacteriaceae species in animal farms. The close relationship of K. pneumoniae isolates from different origins suggests they could serve as a key vehicle for the transfer of ARGs between humans and food animal production environments.
Heterogeneous resistance to colistin in Enterobacter cloacae complex due to a new small transmembrane protein
Authors: Huang Liang , Feng Yu , Zong Zhiyong
Published: May 2019

Background

Enterobacter strains can display heterogeneous resistance (heteroresistance) to colistin but the mechanisms remain largely unknown. We investigated potential mechanisms of colistin heteroresistance in an Enterobacter clinical strain, WCHECl-1060, and found a new mechanism.

Methods

Strain WCHECl-1060 was subjected to WGS to identify known colistin resistance mechanisms. Tn5 insertional mutagenesis, gene knockout and complementation and shotgun cloning were employed to investigate unknown colistin heteroresistance mechanisms. RNA sequencing was performed to link the newly identified mechanism with known ones.

Results

We showed that the phoP gene [encoding part of the PhoP-PhoQ two-component system (TCS)], the dedA(Ecl) gene (encoding an inner membrane protein of the DedA family) and the tolC gene (encoding part of the AcrAB-TolC efflux pump) are required for colistin heteroresistance. We identified a new gene, ecr, encoding a 72 amino acid transmembrane protein, which was able to mediate colistin heteroresistance. We then performed RNA sequencing and transcriptome analysis and found that in the presence of ecr the expression of phoP and the arnBCADTEF operon, which synthesizes and transfers l-Ara4N to lipid A, was increased significantly.

Conclusions

The small protein encoded by ecr represents a new colistin heteroresistance mechanism and is likely to mediate colistin heteroresistance via the PhoP-PhoQ TCS to act on the arnBCADTEF operon.
Common carotid artery ligation at the proximal side before rupture in patients with ligation or occlusion of the external carotid artery at risk of carotid blowout syndrome
Authors: Matsumoto Fumihiko , Matsumura Satoko , Mori Taisuke , Mori Ayaka , Omura Go , Matsumoto Yoshifumi , Fukasawa Masahiko , Kobayashi Kenya , Yoshimoto Seiichi
Published: May 2019

CCA ligation at the proximal side of the bleeding point under local anesthesia and before rupture is a treatment option for patients at high risk of CBS.
Association of Serum Cholesterol Ester Transfer Protein Levels with Taq IB Polymorphism in Acute Coronary Syndrome
Authors: Amer Noha N , Shaaban Gamal M
Published: May 2019

Information on the relationship between circulating cholesteryl ester transfer protein (CETP) levels and coronary heart disease (CHD) incidence (and also, therefore, acute coronary syndrome [ACS]) is conflicting. Many studies have been published concerning this relationship, most of which have incompatible results. In our study, we aimed to determine serum CETP levels in subject individuals with ACS and healthy control individuals, and the association of those levels with Taq IB polymorphism. The current study was conducted with 62 hospitalized patients who had been diagnosed with ACS and 26 controls. All subjects were selected from a previous study of which we are among the coauthors. Serum CETP levels were determined by quantitative enzyme-linked immunosorbent assay (ELISA). The mean serum CETP levels in all patients were significantly higher than those in controls. CETP TaqIB polymorphism affected serum CETP levels, with higher serum CETP for the GA genotype in both groups than in other genotypes. Although the AA genotype showed higher CETP levels than the GG genotype in patients with ACS, the GG showed higher CETP than the AA in healthy controls. Our results support an association between high serum CETP and ACS incidence. Our study helped address some of the controversies regarding the relationship of serum CETP mass to atherosclerosis, in addition to the association of ACS occurrence with circulating CETP levels.
‘Come and See the Blood in the Streets’: Luciano Berio, ‘Coro’, and the Affective Staging of the One-Crowd
Authors: Davis James
Published: May 2019

Luciano Berio’s most substantial work from the 1970s was Coro (1976)—an hour-long piece for chorus and orchestra. This work has attracted a small literature that attempts to understand it in terms of the philosophical framework of the French theorists Gilles Deleuze and Félix Guattari. These Deleuzo-Guattari speculations have remained rather abstract; specifically, they have not attempted to relate the work to the concrete political context of 1970s Italy. This essay attempts to enrich our understanding of Berio by relating the choral work to this political context. In so doing, it will contribute towards a more thorough understanding of the political significance and functioning of the works of one of Italy’s leading composers, and suggest a striking political alignment between his musical production and the radical extra-parliamentary political activity of the 1970s.
Detection of circumstellar helium in Type Iax progenitor systems
Authors: Jacobson-Galán Wynn V , Foley Ryan J , Schwab Josiah , Dimitriadis Georgios , Dong Shawfeng , Jha Saurabh W , Kasen Daniel , Kilpatrick Charles D , Thomas Rollin
Published: May 2019

We present direct spectroscopic modelling of 44 Type Iax supernovae (SNe Iax) using spectral synthesis code SYNAPPS. We confirm detections of helium emission in the early-time spectra of two SNe Iax: SNe 2004cs and 2007J. These He i features are better fit by a pure-emission Gaussian than by a P-Cygni profile, indicating that the helium emission originates from the circumstellar environment rather than the SN ejecta. Based on the modelling of the remaining 42 SNe Iax, we find no obvious helium features in other SN Iax spectra. However, ${\approx } 76{{\ \rm per\ cent}}$ of our sample lack sufficiently deep luminosity limits to detect helium emission with a luminosity of that seen in SNe 2004cs and 2007J. Using the objects with constraining luminosity limits, we calculate that 33 per cent of SNe Iax have detectable helium in their spectra. We examine 11 SNe Iax with late-time spectra and find no hydrogen or helium emission from swept-up material. For late-time spectra, we calculate typical upper limits of stripped hydrogen and helium to be 2 × 10−3 M⊙ and 10−2 M⊙, respectively. While detections of helium in SNe Iax support a white dwarf–He star binary progenitor system (i.e. a single-degenerate [SD] channel), non-detections may be explained by variations in the explosion and ejecta material. The lack of helium in the majority of our sample demonstrates the complexity of SN Iax progenitor systems and the need for further modelling. With strong independent evidence indicating that SNe Iax arise from an SD channel, we caution the common interpretation that the lack of helium or hydrogen emission at late-time in SN Ia spectra rules out SD progenitor scenarios for this class.
Modeling Structural Constraints on Protein Evolution via Side-Chain Conformational States
Authors: Perron Umberto , Kozlov Alexey M , Stamatakis Alexandros , Goldman Nick , Moal Iain H
Published: May 2019

Few models of sequence evolution incorporate parameters describing protein structure, despite its high conservation, essential functional role and increasing availability. We present a structurally aware empirical substitution model for amino acid sequence evolution in which proteins are expressed using an expanded alphabet that relays both amino acid identity and structural information. Each character specifies an amino acid as well as information about the rotamer configuration of its side-chain: the discrete geometric pattern of permitted side-chain atomic positions, as defined by the dihedral angles between covalently linked atoms. By assigning rotamer states in 251,194 protein structures and identifying 4,508,390 substitutions between closely related sequences, we generate a 55-state “Dayhoff-like” model that shows that the evolutionary properties of amino acids depend strongly upon side-chain geometry. The model performs as well as or better than traditional 20-state models for divergence time estimation, tree inference, and ancestral state reconstruction. We conclude that not only is rotamer configuration a valuable source of information for phylogenetic studies, but that modeling the concomitant evolution of sequence and structure may have important implications for understanding protein folding and function.
BioUML: an integrated environment for systems biology and collaborative analysis of biomedical data
Authors: Kolpakov Fedor , Akberdin Ilya , Kashapov Timur , Kiselev llya , Kolmykov Semyon , Kondrakhin Yury , Kutumova Elena , Mandrik Nikita , Pintus Sergey , Ryabova Anna , Sharipov Ruslan , Yevshin Ivan , Kel Alexander
Published: May 2019

BioUML (homepage: http://www.biouml.org, main public server: https://ict.biouml.org) is a web-based integrated environment (platform) for systems biology and the analysis of biomedical data generated by omics technologies. The BioUML vision is to provide a computational platform to build virtual cell, virtual physiological human and virtual patient. BioUML spans a comprehensive range of capabilities, including access to biological databases, powerful tools for systems biology (visual modelling, simulation, parameters fitting and analyses), a genome browser, scripting (R, JavaScript) and a workflow engine. Due to integration with the Galaxy platform and R/Bioconductor, BioUML provides powerful possibilities for the analyses of omics data. The plug-in-based architecture allows the user to add new functionalities using plug-ins. To facilitate a user focus on a particular task or database, we have developed several predefined perspectives that display only those web interface elements that are needed for a specific task. To support collaborative work on scientific projects, there is a central authentication and authorization system (https://bio-store.org). The diagram editor enables several remote users to simultaneously edit diagrams.
Halo concentration, galaxy red fraction, and gas properties of optically defined merging clusters
Authors: Okabe Nobuhiro , Oguri Masamune , Akamatsu Hiroki , Hamabata Akinari , Nishizawa Atsushi J , Medezinski Elinor , Koyama Yusei , Hayashi Masao , Okabe Taizo , Ueda Shutaro , Mitsuishi Ikuyuki , Ota Naomi
Published: May 2019

We present multi-wavelength studies of optically defined merging clusters, based on the Hyper Suprime-Cam Subaru Strategic Program. Luminous red galaxies, tracing cluster mass distributions, enable us to identify cluster subhalos at various merging stages, and thus make a homogeneous sample of cluster mergers that is unbiased with respect to the merger boost of the intracluster medium (ICM). We define, using a peak-finding method, merging clusters with multiple peaks and single clusters with single peaks from the CAMIRA cluster catalog. Stacked weak-lensing analysis indicates that our sample of merging clusters is categorized into major mergers. The average halo concentration for the merging clusters is ∼70% smaller than that of the single-peak clusters, which agrees well with predictions of numerical simulations. The spatial distribution of subhalos is less centrally concentrated than the mass distribution of the main halo. The fractions of red galaxies in the merging clusters are not higher than those of the single-peak clusters. We find a signature of the merger boost of the ICM from the stacked Planck Sunyaev–Zel’dovich effect and ROSAT X-ray luminosity, but not in optical richness. The stacked X-ray surface brightness distribution, aligned with the main subhalo pairs of low-redshift and massive clusters, shows that the central gas core is elongated along the merger axis, and overall gas distribution is misaligned by ∼60°. The homogeneous, unbiased sample of cluster mergers and multi-wavelength follow-up studies provide a unique opportunity to make a complete picture of merger physics over the whole process.
AtCERK1 Phosphorylation Site S493 Contributes to the Transphosphorylation of Downstream Components for Chitin-Induced Immune Signaling
Authors: Suzuki Maruya , Yoshida Issei , Suto Kenkichi , Desaki Yoshitake , Shibuya Naoto , Kaku Hanae
Published: May 2019

While ligand-induced autophosphorylation of receptor-like kinases (RLKs) is known to be critical for triggering the downstream responses, biochemical mechanism by which each phosphorylation site contributes to the initiation of corresponding signaling cascades is only poorly understood, except the involvement of some phosphorylation sites in the regulation of catalytic activity of these RLKs. In this article, we first confirmed that the phosphorylation of S493 of AtCERK1 is involved in the regulation of chitin-induced defense responses by the complementation of an atcerk1 mutant with AtCERK1(S493A) cDNA. In vitro kinase assay with the heterologously expressed kinase domain of AtCERK1, GST-AtCERK1cyt, showed that the S493A mutation did not affect the autophosphorylation of AtCERK1 itself but diminished the transphosphorylation of downstream signaling components, PBL27 and PUB4. On the other hand, a phosphomimetic mutant, GST-AtCERK1(S493D)cyt, transphosphorylated these substrates as similar to the wild type AtCERK1. These results suggested that the phosphorylation of S493 does not contribute to the regulation of catalytic activity but plays an important role for the transphosphorylation of the downstream signaling components, thus contributing to the initiation of chitin signaling. To our knowledge, it is a novel finding that a specific phosphorylation site contributes to the regulation of transphosphorylation activity of RLKs. Further studies on the structural basis by which S493 phosphorylation contributes to the regulation of transphosphorylation would contribute to the understanding how the ligand-induced autophosphorylation of RLKs properly regulates the downstream signaling.
Automatic plankton quantification using deep features
Authors: González Pablo , Castaño Alberto , Peacock Emily E , Díez Jorge , Del Coz Juan José , Sosik Heidi M
Published: May 2019

The study of marine plankton data is vital to monitor the health of the world’s oceans. In recent decades, automatic plankton recognition systems have proved useful to address the vast amount of data collected by specially engineered in situ digital imaging systems. At the beginning, these systems were developed and put into operation using traditional automatic classification techniques, which were fed with hand-designed local image descriptors (such as Fourier features), obtaining quite successful results. In the past few years, there have been many advances in the computer vision community with the rebirth of neural networks. In this paper, we leverage how descriptors computed using convolutional neural networks trained with out-of-domain data are useful to replace hand-designed descriptors in the task of estimating the prevalence of each plankton class in a water sample. To achieve this goal, we have designed a broad set of experiments that show how effective these deep features are when working in combination with state-of-the-art quantification algorithms.
Impact of flare on radiographic progression after etanercept continuation, tapering or withdrawal in patients with rheumatoid arthritis
Authors: Smolen Josef S , Pedersen Ronald , Jones Heather , Mahgoub Ehab , Marshall Lisa
Published: May 2019

Objectives

The structural consequences of flare after dose reduction/discontinuation of biologic DMARDs in patients with RA who achieve remission are unclear. We compared the incidence of radiographic progression in patients with RA who did and did not experience flare after etanercept (ETN) reduction/withdrawal.

Methods

Eligible adults with moderately active RA despite MTX received ETN 50 mg plus MTX weekly in a 36-week, open-label induction period; patients achieving sustained low disease activity by week 36 were randomized to ETN 50 mg plus MTX, ETN 25 mg plus MTX, or placebo plus MTX in a 52-week, double-blind maintenance period. In post hoc analyses, radiographic progression (Δ modified total Sharp score ⩾0.5 units/year) was compared in patients with and without flare [based on DAS28 relapse (main analysis), and clinical disease activity index and simplified disease activity index relapse (sensitivity analyses)]. Findings from patients receiving full- and reduced-dose combination therapy were pooled for comparison with those from patients receiving MTX only.

Results

Significantly more patients receiving MTX monotherapy experienced flare, defined as DAS28 relapse (62% vs 21%; P < 0.0001) and radiographic progression (17% vs 9%; P < 0.001), than patients receiving full-/reduced-dose combination therapy in the double-blind period. Patients with flare defined as clinical disease activity index and simplified disease activity index relapse had higher rates of radiographic progression than those without flare in the full-/reduced-dose combination therapy group (P < 0.01).

Conclusion

Radiographic progression may be a consequence of flare after biologic DMARD dose reduction/withdrawal in patients with RA. If these approaches are taken, careful monitoring for signs/symptoms of relapse is needed.

Trial registration

ClinicalTrials.gov, https://clinicaltrials.gov, NCT00565409.
Dissecting the functions of NIPBL using genome editing: The importance of the N-terminus of NIPBL in transcriptional regulation
Authors: Izumi Kosuke , Akiyama Kazuhiro , Fujiki Katsunori , Masuda Koji , Nakato Ryuichiro , Otsubo Aiko , Bando Masashige , Shirahige Katsuhiko
Published: May 2019

Cornelia de Lange syndrome (CdLS) is characterized by craniofacial dysmorphisms, intellectual disabilities, growth retardation, and several other systemic abnormalities. CdLS is caused by heterozygous germline mutations in structural and regulatory components of cohesin. Mutations in NIPBL, which encodes regulatory subunit of cohesin, are frequently found in individuals with CdLS. CdLS is associated with a currently unknown mechanism of global transcriptional dysregulation. In this study, NIPBL mutants were generated using the CRISPR/Cas9 system to study this mechanism. Clones with a biallelic frameshift mutation in exon 3 of NIPBL, resulting in a truncated N-terminus, displayed transcriptional dysregulation without sister chromatid separation defects. Detailed transcriptome analysis revealed the overexpression of genes in NIPBL mutants that are typically expressed at low levels in wild type and the reduced expression of genes that are typically expressed at high levels in wild type. This result suggested that NIPBL plays a role in fine-tuning gene expression levels. MAU2 protein, that closely interacts with NIPBL, was nearly absent in these clones. The reduction of MAU2 observed in NIPBL mutants points to the importance of the NIPBL N-terminus/MAU2 interaction in transcriptional regulatory role of NIPBL.
Estimation of biodiversity metrics by environmental DNA metabarcoding compared with visual and capture surveys of river fish communities
Authors: Doi Hideyuki , Inui Ryutei , Matsuoka Shunsuke , Akamatsu Yoshihisa , Goto Masuji , Kono Takanori
Published: May 2019

Information on alpha (local), beta (between habitats), and gamma (regional) diversity is fundamental to understanding biodiversity as well as the function and stability of community dynamics. Methods like environmental DNA (eDNA) metabarcoding are currently considered useful to investigate biodiversity.

We compared the performance of eDNA metabarcoding with visual and capture surveys for estimating alpha and gamma diversity of river fish communities, and nestedness and turnover in particular.

In five rivers across west Japan, by comparison to visual/capture surveys, eDNA metabarcoding detected more species in the study sites (i.e., alpha diversity). Consequently the overall number of species in the region (i.e., gamma diversity) was higher. In particular, the species found by visual/capture surveys were encompassed by those detected by eDNA metabarcoding.

Estimates of community diversity within rivers differed between survey methods. Although we found that the methods show similar levels of community nestedness and turnover within the rivers, visual/capture surveys showed more distinct community differences from upstream to downstream. Our results suggest that eDNA metabarcoding may be a suitable method for community assemblage analysis, especially for understanding regional community patterns, for fish monitoring in rivers.
Demonstration of different entity of appendicitis and related causes of disease through study of cluster/outbreak: Systematic Review and Meta Analysis
Authors: Guo Yi-Tian , Liu Guo-Zhen , Tan Shi-Yun , Guo Yi
Published: May 2019

Objective

To demonstrate different entities of appendicitis and causal association between microbiota and different types of appendicitis through studying cluster/outbreak, and providing guidance to find new cluster/outbreak of appendicitis and the epidemiological evidences of infectious etiology of appendicitis.

Data Sources

PubMed, Embase, CNKI, WanFang, VIP, CBM from their establishment to Jan, 2019, and the references lists from retrieved reports.

Study Eligibility

Reports on cluster/outbreak of appendicitis and reports of case series occurring in cluster/outbreak worldwide according to CDC’s definition of cluster/outbreak.

Data Extraction and Synthesis

Two researchers independently assessed report quality and extracted data according to Moose. We used random effect model for meta-analysis by Meta-Analyst ß3.13 software. Study-level assessment was conducted according to investigation methods introduced by Reingold and outcome-level assessment by GRADE system. We selected outcome measures before data collection began.

Results

We included 10 clusters/outbreaks of appendicitis from China and USA with total 626 patients. We demonstrated two entities, type 1 appendicitis (455 patients) and type 2 appendicitis (151patients). 20 patients left were unclassified type. For type 1 appendicitis, Natural history showed progression from a non-perforated appendicitis to perforated appendicitis as described traditionally. More than 88% of patients had elevated body temperature, WBC and neutrophil percentage. For type 2 appendicitis, natural history showed that only a few patients developed into phlegmonous appendicitis (6.9%,) or acute gangrenous appendicitis (1.4%) and no perforation or periappendicular abscess. More than 78% of patients had normal body temperature, WBC and NP. The patients’ time of type 1 appendicitis is shorter than that of type 2 appendicitis. Type 2 appendicitis had different histological features from type 1 appendicitis and was associated with fusobacteria. 9 of 10 cluster/outbreak occurred in group living unity such as school and camps, and many of them showed features of infectious diseases. The bodies of evidence were high quality in Meta analysis.

Conclusion

Cluster/outbreak of appendicitis is more often than expected worldwide and occurred in group living unity. Sporadic perforated appendicitis and non-perforated appendicitis may be not two different entities, but different stages of a same entity, which is inconsistent with modern classification of appendicitis. Type 2 appendicitis is a new entities. Studying cluster/outbreak is a new method in finding of new entity and causal association between microbiota and different types of appendicitis. Epidemiological evidence supported infectious etiology of appendicitis.
Emergence and Genetic Analysis of Avian Gyrovirus 2 Variants-RelatedGyrovirusin Farmed King-ratsnakes (Elaphe carinata): the First Report in China
Authors: Wu Qianqian , Chen Qinxi , Hu Wen , Wang Xueyu , Ji Jun
Published: May 2019

Avian gyrovirus 2 (AGV2), which is similar to chicken infectious anemia virus, is a new member of theCircovirusgenus. AGV2 has been detected not only in chicken but also in human tissues and feces. In this study, a total of 91 samples (8 liver tissues and 83 faecal samples) collected from king-ratsnakes (Elaphe carinata) at 7 separate farms in Hubei and Henan, China, were analyzed to detect AGV2 DNA via specific PCR. The results indicated a low positive rate of AGV2 (6.59%, 6/91) in the studied animals, and all of the positive samples were from the same farm. The AGV2 strain HB2018S1 was sequenced, and the genome with a total length of 2376 nt contained three partially overlapping open reading frames: VP1, VP2, and VP3. Phylogenetic tree analysis revealed that the HB2018S1, NX1506-1 strain from chickens in China belong to the same clade, with nucleotide homology as high as 99.5%. In total, 10 amino acid mutation sites, including 44R/K, 74T/A, 256 C/R, 279L/Q, and 373V/A in AGV2 VP1; 60I/T, 125T/I, 213D/N, and 215L/S in AGV2 VP2; and 83H/Y in AGV2 VP3, were found in the genome of HB2018S1 that were different from those observed in most reference strains, suggesting that the differences are related to an transboundary movement among hosts which needs to be further elucidated.

IMPORTANCE

Recently, AGV2 has been detected in live poultry markets and human blood in mainland China. Previous findings indicated future studies should investigate the large geographic distribution of AGV2 and monitor the variants, the host range, and the associated diseases. To the best of our knowledge, this study is the first report on AGV2 infected poikilotherm, suggested that cross-host transmission of viruses with circular single-stranded DNA genomes would be a public health concern.
How well do routine molecular diagnostics detect rifampicin heteroresistance inMycobacterium tuberculosis?
Authors: Ng Kamela C. S. , Supply Philip , Cobelens Frank G. J. , Gaudin Cyril , Gonzalez-Martin Julian , de Jong Bouke C. , Rigouts Leen
Published: May 2019

Rifampicin heteroresistance – where rifampicin-resistant and -susceptible tuberculosis (TB) bacilli co-exist – may result in failed standard TB treatment and potential spread of rifampicin-resistant strains. Detection of rifampicin heteroresistance in routine rapid diagnostic tests (RDTs) allows for patients to receive prompt and effective multidrug-resistant-TB treatment, and may improve rifampicin-resistant TB control.

The limit of detection (LOD) of rifampicin heteroresistance for phenotypic drug susceptibility testing by the proportion method is 1%, yet is insufficiently documented for RDTs. We therefore aimed to determine, for the four RDTs (XpertMTB/RIF, XpertMTB/RIF Ultra, GenoTypeMTBDRplusv2.0, and GenoscholarNTM+MDRTBII), the LOD per probe and mutation, validated by colony-forming-unit-counting and targeted deep sequencing (Deeplex-MycTB).

We selected one rifampicin-susceptible and four rifampicin-resistant strains, with mutation D435V, H445D, H445Y, and S450L respectively, mixed them in various proportions in triplicate, tested them with each RDT, and determined the LODs per mutation type. Deeplex-MycTB revealed concordant proportions of the minority resistant variants in the mixtures. The Deeplex-MycTB-validated-LODs ranged from 20-80% for XpertMTB/RIF, 20-70% for Xpert Ultra, 5-10% for GenoTypeMTBDRplusv2.0, and 1-10% for GenoscholarNTM+MTBII for the different mutations.

Deeplex-MycTB, GenoTypeMTBDRplusv2.0, and GenoscholarNTM+MDRTBII, provide explicit information on rifampicin heteroresistance for the most frequently detected mutations. Classic Xpert and Ultra report rifampicin heteroresistance as rifampicin resistance, while Ultra may denote rifampicin heteroresistance through ‘mixed patterns’ of wild-type and mutant melt probe melt peak temperatures.

Overall, our findings inform end-users that the threshold for reporting resistance in case of rifampicin heteroresistance is the highest for Classic Xpert and Ultra, to resolve phenotypic and genotypic discordant rifampicin-resistant TB results.
Novel cytokinetic ring components drive negative feedback in cortical contractility
Authors: Bell Kathryn Rehain , Werner Michael E. , Doshi Anusha , Cortes Daniel B. , Sattler Adam , Vuong-Brender Thanh , Labouesse Michel , Maddox Amy Shaub
Published: May 2019

Actomyosin cortical contractility drives many cell shape changes including cytokinetic furrowing. While positive regulation of contractility is well characterized, counterbalancing negative regulation and mechanical brakes are less well understood. The small GTPase RhoA is a central regulator, activating cortical actomyosin contractility during cytokinesis and other events. Here we report how two novel cytokinetic ring components, GCK-1 and CCM-3, participate in a negative feedback loop among RhoA and its cytoskeletal effectors to inhibit contractility. GCK-1 and CCM-3 are recruited by active RhoA and anillin to the cytokinetic ring, where they in turn limit RhoA activity and contractility. This is evidenced by increased RhoA activity, anillin and non-muscle myosin II in the cytokinetic ring, and faster cytokinetic furrowing, following depletion of GCK-1 or CCM-3. GCK-1 or CCM-3 depletion also reduced RGA-3 levels in pulses, and increased baseline RhoA activity and pulsed contractility during zygote polarization. Together, our findings suggest that GCK-1 and CCM-3 regulate cortical actomyosin contractility via negative feedback.

Novel cytokinetic ring proteins, the Ste20 family kinase GCK-1 and its heterodimeric cofactor Cerebral Cavernous Malformations-3, close a negative feedback loop involving the RhoA GAP RGA-3/4, RhoA, and its cytoskeletal effector anillin to limit actomyosin contractility in cytokinesis and during polarization of the C. elegans zygote.
Computational Analysis of Therapeutic Neuroadaptation to Chronic Antidepressant in a Model of the Monoaminergic Neurotransmitter and Stress Hormone Systems
Authors: Camacho Mariam Bonyadi , Vijitbenjaronk Warut D. , Anastasio Thomas J
Published: May 2019

The clinical practice of selective serotonin reuptake inhibitor (SSRI) augmentation relies heavily on clinical judgment and trial-and-error. Unfortunately, the drug combinations prescribed today fail to provide relief for all treatment-resistant depressed patients. In order to identify potentially more effective treatments, we developed a computational model of the monoaminergic neurotransmitter and stress-steroid systems that neuroadapts to chronic administration of combinations of antidepressant drugs and hormones by adjusting the strengths of its transmitter-system components (TSCs). We used the model to screen 60 chronically administered drug/hormone pairs and triples, and identified as potentially therapeutic those combinations that raised the monoamines (serotonin, norepinephrine, and dopamine) but lowered cortisol following neuroadaptation in the model. We also evaluated the contributions of individual and pairs of TSCs to therapeutic neuroadaptation with chronic SSRI using sensitivity, correlation, and linear temporal-logic analyses. All three approaches found that therapeutic neuroadaptation to chronic SSRI is an overdetermined process that depends on multiple TSCs, providing a potential explanation for the clinical finding that no single antidepressant regimen alleviates depressive symptoms in all patients.
Fine-scale haplotype structure reveals strong signatures of positive selection in a recombining bacterial pathogen
Authors: Arnold Brian , Sohail Mashaal , Wadsworth Crista , Corander Jukka , Hanage William P. , Sunyaev Shamil , Grad Yonatan H.
Published: May 2019

Identifying the forces that create and shape ecologically meaningful variation in bacteria remains an important challenge. For recombining bacteria, the sign and strength of linkage provide a unique lens into ongoing selection. We show derived alleles less than 300bp apart inNeisseria gonorrhoeaeexhibit more coupling linkage than repulsion linkage, a pattern that cannot be explained by limited recombination or neutrality as these couplings are significantly stronger for nonsynonymous alleles compared to synonymous alleles. While linkage is shaped by many evolutionary processes, extensive simulations show only two distinct forms of positive selection can drive an excess of coupling linkage between neighboring nonsynonymous alleles: directional selection on introgressed alleles or selection that maintains distinct haplotypes in the presence of recombination. Our results establish a framework for identifying patterns of selection in fine-scale haplotype structure that indicate specific ecological processes in species that recombine with distantly related lineages or possess coexisting adaptive haplotypes.
Differential Functions of Splicing Factors in Breast-Cancer Initiation and Metastasis
Authors: Das Shipra , Akerman Martin , Park SungHee , Brugioli Mattia , Geier Adam , Kesarwani Anil K. , Fan Martin , Leclair Nathan , Urbanski Laura , Lin Kuan-Ting , Hu Chenle , Hua Xingan , George Joshy , Muthuswamy Senthil K. , Krainer Adrian R. , Anczuków Olga
Published: May 2019

Misregulation of alternative splicing is a hallmark of human tumors; yet to what extent and how it contributes to malignancy are only beginning to be unraveled. Here, we define which members of the splicing factor SR and SR-like families contribute to breast cancer, and uncover differences and redundancies in their targets and biological functions. We first identify splicing factors frequently altered in human breast tumors, and then assay their oncogenic functions using breast organoid models. Importantly we demonstrate that not all splicing factors affect mammary tumorigenesis. Specifically, upregulation of either SRSF4, SRSF6 or TRA2β promotes cell transformation and invasion. By characterizing the targets of theses oncogenic factors, we identify a shared set of spliced genes associated with well-established cancer hallmarks. Finally, we demonstrate that the splicing factor TRA2β is regulated by the MYC oncogene, plays a role in metastasis maintenancein vivo, and its levels correlate with breast-cancer-patient survival.