Mining network-level properties of Twitter altmetrics data

© 2019, Akadémiai Kiadó, Budapest, Hungary. Social networking sites play a significant role in altmetrics. While 90% of all altmetric mentions come from Twitter, the known microscopic and macroscopic properties of Twitter altmetrics data are limited. In this study, we present a large-scale analysis of Twitter altmetrics data using social network analysis techniques on the ‘mention’ network of Twitter users. Exploiting the network-level properties of over 1.4 million tweets, corresponding to 77,757 scholarly articles, this study focuses on the following aspects of Twitter altmetrics data: (a) the influence of organizational accounts; (b) the formation of disciplinary communities; (c) the cross-disciplinary interaction among Twitter users; (d) the network motifs of influential Twitter users; and (e) testing the small-world property. The results show that Twitter-based social media communities have unique characteristics, which may affect social media usage counts either directly or indirectly. Therefore, instead of treating altmetrics data as a black box, the underlying social media networks, which may either inflate or deflate social media usage counts, need further scrutiny

Speaking the host language: how Salmonella effector proteins manipulate the host

Salmonella injects over 40 virulence factors, termed effectors, into host cells to subvert diverse host cellular processes. Of these 40 Salmonella effectors, at least 25 have been described as mediating eukaryotic-like, biochemical post-translational modifications (PTMs) of host proteins, altering the outcome of infection. The downstream changes mediated by an effector's enzymatic activity range from highly specific to multifunctional, and altogether their combined action impacts the function of an impressive array of host cellular processes, including signal transduction, membrane trafficking, and both innate and adaptive immune responses. Salmonella and related Gram-negative pathogens have been a rich resource for the discovery of unique enzymatic activities, expanding our understanding of host signalling networks, bacterial pathogenesis as well as basic biochemistry. In this review, we provide an up-to-date assessment of host manipulation mediated by the Salmonella type III secretion system injectosome, exploring the cellular effects of diverse effector activities with a particular focus on PTMs and the implications for infection outcomes. We also highlight activities and functions of numerous effectors that remain poorly characterized

Neuroimaging of Inflammation in Memory and Related Other Disorders (NIMROD) study protocol: a deep phenotyping cohort study of the role of brain inflammation in dementia, depression and other neurological illnesses

$\textit{Introduction}$ Inflammation of the central nervous system is increasingly regarded as having a role in cognitive disorders such as dementia and depression, but it is not clear how such neuroinflammation relates to other aspects of neuropathology (e.g., tau and amyloid pathology) as well as to structural and functional changes in the brain and symptoms (as assessed via MRI and clinical and neuropsychological assessment). This study will explore these pathophysiological mechanisms using positron emission tomography (PET) which allows $\textit{in vivo}$ imaging of inflammation, amyloid and tau deposition, together with neuropsychological profiling, magnetic resonance imaging (MRI) and peripheral biomarker analysis. \textit{Methods & analysis} Using PET imaging of the ligand [11C]PK11195 we will test for increased neuroinflammation $\textit{in vivo}$ in patients with Alzheimer’s disease, Lewy body dementia, frontotemporal dementia, progressive supranuclear palsy, late onset depression and mild cognitive impairment, when compared to healthy controls. We will assess whether areas of inflammatory change are associated with amyloid and tau deposition (assessed using $^{11}$C-labelled Pittsburgh Compound B ([$^{11}$C]PiB) and $^{18}$F-labelled AV-1451 respectively), as well as structural and functional connectivity changes found on MRI. Inflammatory biomarker analysis and immune-phenotyping of peripheral blood monocytes will determine the correlation between central (i.e., neural) and peripheral inflammation. Finally, we will examine whether neuroinflammatory changes seen on PET imaging are associated with global and domain specific cognitive impairments, or predict cognitive decline over 12 months. \textit{Ethics & dissemination} The study protocol was approved by the local ethics committee, East of England - Cambridge Central Research Ethics Committee (reference: 13/EE/0104). The study is also ARSAC approved as part of this process. Data will be disseminated by presentation at national and international conferences and by publication, predominantly in journals of neuroscience as well as clinical neurology and psychiatry. $\textit{Strengths}$ Multimodal deep phenotyping Comparisons between diseases as well as with controls Longitudinal neuropsychology data Comparison of central and peripheral inflammation $\textit{Weaknesses}$ Lack of longitudinal neuroimaging Not a prospective study, unable to assess causationThe study is funded by the UK National Institute of Health Research Cambridge Biomedical Research Unit in Dementia (Project 4 - RNAG/293). JBR is supported by the Wellcome Trust (103838). JPC is supported by the UK National Institute of Health Research Biomedical Research Centre at Cambridge. PVR is supported by the PSP Association

The alpha 7 nicotinic receptor agonist PHA-543613 hydrochloride inhibits <i>Porphyromonas gingivalis</i>-induced expression of interleukin-8 by oral keratinocytes

Objective: The alpha 7 nicotinic receptor (α7nAChR) is expressed by oral keratinocytes. α7nAChR activation mediates anti-inflammatory responses. The objective of this study was to determine if α7nAChR activation inhibited pathogen-induced interleukin-8 (IL-8) expression by oral keratinocytes.&lt;p&gt;&lt;/p&gt; Materials and methods: Periodontal tissue expression of α7nAChR was determined by real-time PCR. OKF6/TERT-2 oral keratinocytes were exposed to &lt;i&gt;Porphyromonas gingivalis&lt;/i&gt; in the presence and absence of a α7nAChR agonist (PHA-543613 hydrochloride) alone or after pre-exposure to a specific α7nAChR antagonist (α-bungarotoxin). Interleukin-8 (IL-8) expression was measured by ELISA and real-time PCR. Phosphorylation of the NF-κB p65 subunit was determined using an NF-κB p65 profiler assay and STAT-3 activation by STAT-3 in-cell ELISA. The release of ACh from oral keratinocytes in response to &lt;i&gt;P. gingivalis&lt;/i&gt; lipopolysaccharide was determined using a GeneBLAzer M3 CHO-K1-blacell reporter assay.&lt;p&gt;&lt;/p&gt; Results: Expression of α7nAChR mRNA was elevated in diseased periodontal tissue. PHA-543613 hydrochloride inhibited &lt;i&gt;P. Gingivalis&lt;/i&gt;-induced expression of IL-8 at the transcriptional level. This effect was abolished when cells were pre-exposed to a specific α7nAChR antagonist, α-bungarotoxin. PHA-543613 hydrochloride downregulated NF-κB signalling through reduced phosphorylation of the NF-κB p65-subunit. In addition, PHA-543613 hydrochloride promoted STAT-3 signalling by maintenance of phosphorylation. Furthermore, oral keratinocytes upregulated ACh release in response to &lt;i&gt;P. Gingivalis&lt;/i&gt; lipopolysaccharide.&lt;p&gt;&lt;/p&gt; Conclusion: These data suggest that α7nAChR plays a role in regulating the innate immune responses of oral keratinocytes.&lt;p&gt;&lt;/p&gt

Acquisition of the Sda1-encoding bacteriophage does not enhance virulence of the serotype M1 Streptococcus pyogenes strain SF370

The resurgence of invasive disease caused by Streptococcus pyogenes (group A Streptococcus [GAS]) in the past 30 years has paralleled the emergence and global dissemination of the highly virulent M1T1 clone. The GAS M1T1 clone has diverged from the ancestral M1 serotype by horizontal acquisition of two unique bacteriophages, encoding the potent DNase Sda1/SdaD2 and the superantigen SpeA, respectively. The phage-encoded DNase promotes escape from neutrophil extracellular traps and is linked to enhanced virulence of the M1T1 clone. In this study, we successfully used in vitro lysogenic conversion to transfer the Sda1-encoding phage from the M1T1 clonal strain 5448 to the nonclonal M1 isolate SF370 and determined the impact of this horizontal gene transfer event on virulence. Although Sda1 was expressed in SF370 lysogens, no capacity of the phage-converted strain to survive human neutrophil killing, switch to a hyperinvasive covRS mutant form, or cause invasive lethal infection in a humanized plasminogen mouse model was observed. This work suggests that the hypervirulence of the M1T1 clone is due to the unique synergic effect of the M1T1 clone bacteriophage-specific virulence factor Sda1 acting in concert with the M1T1 clone-specific genetic scaffold

Protective effect of stromal Dickkopf-3 in prostate cancer: opposing roles for TGFBI and ECM-1

Aberrant transforming growth factor–β (TGF-β) signaling is a hallmark of the stromal microenvironment in cancer. Dickkopf-3 (Dkk-3), shown to inhibit TGF-β signaling, is downregulated in prostate cancer and upregulated in the stroma in benign prostatic hyperplasia, but the function of stromal Dkk-3 is unclear. Here we show that DKK3 silencing in WPMY-1 prostate stromal cells increases TGF-β signaling activity and that stromal cellconditioned media inhibit prostate cancer cell invasion in a Dkk-3-dependent manner. DKK3 silencing increased the level of the cell-adhesion regulator TGF-β–induced protein (TGFBI) in stromal and epithelial cell-conditioned media, and recombinant TGFBI increased prostate cancer cell invasion. Reduced expression of Dkk-3 in patient tumors was associated with increased expression of TGFBI. DKK3 silencing reduced the level of extracellular matrix protein-1 (ECM-1) in prostate stromal cell-conditioned media but increased it in epithelial cell-conditioned media, and recombinant ECM-1 inhibited TGFBI-induced prostate cancer cell invasion. Increased ECM1 and DKK3 mRNA expression in prostate tumors was associated with increased relapse-free survival. These observations are consistent with a model in which the loss of Dkk-3 in prostate cancer leads to increased secretion of TGFBI and ECM-1, which have tumor-promoting and tumor-protective roles, respectively. Determining how the balance between the opposing roles of extracellular factors influences prostate carcinogenesis will be key to developing therapies that target the tumor microenvironment

Debris Disks: Probing Planet Formation

Debris disks are the dust disks found around ~20% of nearby main sequence stars in far-IR surveys. They can be considered as descendants of protoplanetary disks or components of planetary systems, providing valuable information on circumstellar disk evolution and the outcome of planet formation. The debris disk population can be explained by the steady collisional erosion of planetesimal belts; population models constrain where (10-100au) and in what quantity (>1Mearth) planetesimals (>10km in size) typically form in protoplanetary disks. Gas is now seen long into the debris disk phase. Some of this is secondary implying planetesimals have a Solar System comet-like composition, but some systems may retain primordial gas. Ongoing planet formation processes are invoked for some debris disks, such as the continued growth of dwarf planets in an unstirred disk, or the growth of terrestrial planets through giant impacts. Planets imprint structure on debris disks in many ways; images of gaps, clumps, warps, eccentricities and other disk asymmetries, are readily explained by planets at >>5au. Hot dust in the region planets are commonly found (<5au) is seen for a growing number of stars. This dust usually originates in an outer belt (e.g., from exocomets), although an asteroid belt or recent collision is sometimes inferred.Comment: Invited review, accepted for publication in the 'Handbook of Exoplanets', eds. H.J. Deeg and J.A. Belmonte, Springer (2018

Sarcoidosis activates diverse transcriptional programs in bronchoalveolar lavage cells

Abstract Background Sarcoidosis is a multisystem immuno-inflammatory disorder of unknown etiology that most commonly involves the lungs. We hypothesized that an unbiased approach to identify pathways activated in bronchoalveolar lavage (BAL) cells can shed light on the pathogenesis of this complex disease. Methods We recruited 15 patients with various stages of sarcoidosis and 12 healthy controls. All subjects underwent bronchoscopy with lavage. For each subject, total RNA was extracted from BAL cells and hybridized to an Affymetrix U133A microarray. Rigorous statistical methods were applied to identify differential gene expression between subjects with sarcoidosis vs. controls. To better elucidate pathways differentially activated between these groups, we integrated network and gene set enrichment analyses of BAL cell transcriptional profiles. Results Sarcoidosis patients were either non-smokers or former smokers, all had lung involvement and only two were on systemic prednisone. Healthy controls were all non-smokers. Comparison of BAL cell gene expression between sarcoidosis and healthy subjects revealed over 1500 differentially expressed genes. Several previously described immune mediators, such as interferon gamma, were upregulated in the sarcoidosis subjects. Using an integrative computational approach we constructed a modular network of over 80 gene sets that were highly enriched in patients with sarcoidosis. Many of these pathways mapped to inflammatory and immune-related processes including adaptive immunity, T-cell signaling, graft vs. host disease, interleukin 12, 23 and 17 signaling. Additionally, we uncovered a close association between the proteasome machinery and adaptive immunity, highlighting a potentially important and targetable relationship in the pathobiology of sarcoidosis. Conclusions BAL cells in sarcoidosis are characterized by enrichment of distinct transcriptional programs involved in immunity and proteasomal processes. Our findings add to the growing evidence implicating alveolar resident immune effector cells in the pathogenesis of sarcoidosis and identify specific pathways whose activation may modulate disease progression

NMR Analysis of the Dynamic Exchange of the NS2B Cofactor between Open and Closed Conformations of the West Nile Virus NS2B-NS3 Protease

Dengue and West Nile virus infections put an estimated 2.5 billion people at risk. Neither drugs nor vaccines are currently available against these diseases. The non-structural protein NS3 is a protease that, together with the cofactor NS2B, is essential for viral maturation. The NS2B-NS3 proteases of dengue and West Nile viruses are highly homologous and present promising drug targets. Crystal structures of the West Nile virus protease with and without bound inhibitor revealed large structural differences in NS2B, while no crystal structure of the dengue virus protease could be determined with a bound inhibitor. We investigated the structural change in solution and found that the C-terminal segment (CTS) of the NS2B cofactor is prone to dissociation from NS3. In the case of the West Nile virus protease, the CTS of NS2B is mostly associated with NS3, especially in the presence of inhibitors. In the case of the dengue virus protease and in the absence of inhibitors, the CTS of NS2B is mostly dissociated from NS3. Finding drug candidates to inhibit the association of the NS2B cofactor may thus be easier for the dengue virus protease