bluuebunny/crossref_metadata_2025_split huggingface dataset:
The RHIM within the M45 protein from murine cytomegalovirus forms heteromeric amyloid fibrils with RIPK1 and RIPK3
Authors: Pham Chi L. L. , Strange Merryn , O’ Carroll Ailis , Shanmugam Nirukshan , Sierecki Emma , Gambin Yann , Steain Megan , Sunde Margaret 
Published: May 2018

AbstractThe M45 protein from murine cytomegalovirus protects infected murine cells from death by necroptosis and can protect human cells from necroptosis induced by TNFR activation, when heterologously expressed. We show that the N-terminal 90 residues of the M45 protein, which contain a RIP Homotypic Interaction Motif (RHIM), are sufficient to confer protection against TNFR-induced necroptosis. This N-terminal region of M45 drives rapid self-assembly into homo-oligomeric amyloid fibrils and interacts with the RHIMs of human RIPK1 and RIPK3 kinases to form heteromeric amyloid fibrils in vitro. An intact RHIM core tetrad is required for the inhibition of cell death by M45 and we show that mutation of those key tetrad residues abolishes homo- and hetero-amyloid assembly by M45 in vitro, suggesting that the amyloidogenic nature of the M45 RHIM underlies its biological activity. Our results indicate that M45 mimics the interactions made by RIPK1 with RIPK3 in forming heteromeric amyloid structures.
Generation of the squamous epithelial roof of the 4thventricle
Authors: Campo-Paysaa Florent , Clarke Jonathan DW , Wingate Richard JT 
Published: May 2018

SummaryWe use the transparency of zebrafish embryos to reveal thede novogeneration of a simple squamous epithelium and identify the cellular architecture in the epithelial transition zone that ties this squamous epithelium to the columnar neuroepithelium within the embryo’s brain. The simple squamous epithelium of the rhombencephalic roof plate is pioneered by distinct mesenchymal cells at the dorsal midline of the neural tube. Subsequently a progenitor zone is established at the interface between columnar epithelium of the rhombic lip and the expanding squamous epithelium of the roof plate. Surprisingly this interface consists of a single progenitor cell type that we have named the veil cell. Veil cells expressgdf6aand constitute a lineage restricted stem zone that generates the squamous roof plate by direct transformation and asymmetrically fated divisions. Experimental restriction of roof plate expansion leads to extrusion of veil cell daughters and squamous cells, suggesting veil cell fate is regulated by the space available for roof plate growth.
Sera from individuals with narrowly focused influenza virus antibodies rapidly select viral escape mutationsin ovo
Authors: Davis Amy K.F. , McCormick Kevin , Gumina Megan E. , Petrie Joshua G. , Martin Emily T. , Xue Katherine S. , Bloom Jesse D. , Monto Arnold S. , Bushman Frederic D. , Hensley Scott E. 
Published: May 2018

AbstractInfluenza viruses use distinct antibody escape mechanisms depending on the overall complexity of the antibody response that is encountered. When grown in the presence of a hemagglutinin (HA) monoclonal antibody, influenza viruses typically acquire a single HA mutation that reduces the binding of that specific monoclonal antibody. In contrast, when confronted with mixtures of HA monoclonal antibodies or polyclonal sera that have antibodies that bind several HA epitopes, influenza viruses acquire mutations that increase HA binding to host cells. Recent data from our laboratory and others suggest that some humans possess antibodies that are narrowly focused on HA epitopes that were present in influenza virus strains that they were likely exposed to in childhood. Here, we completed a series of experiments to determine if humans with narrowly focused HA antibody responses are able to select for influenza virus antigenic escape variantsin ovo.We identified three human donors that possessed HA antibody responses that were heavily focused on a single HA antigenic site. Remarkably, sera from all three of these donors selected single HA escape mutations duringin ovopassage experiments, similar to what has been previously reported for single monoclonal antibodies. These single HA mutations directly reduced binding of serum antibodies used for selection. We propose that new antigenic variants of influenza viruses might originate in individuals that produce antibodies that are narrowly focused on HA epitopes that were present in viral strains that they encountered in childhood.ImportanceInfluenza vaccine strains must be updated frequently since circulating viral strains continuously change in antigenically important epitopes. Our previous studies have demonstrated that some individuals possess antibody responses that are narrowly focused on epitopes that were present in viral strains that they encountered during childhood. Here, we show that influenza viruses rapidly escape this type of polyclonal antibody response when grownin ovoby acquiring single mutations that directly prevent antibody binding. These studies improve our understanding of how influenza viruses evolve when confronted with narrowly focused polyclonal human antibodies.
Establishment and Application of a duplex real-time qPCR method for detection ofSalmonellaspp. andSerratia fonticolain imported feedstuffs
Authors: Ruan Jing hua , Wang Wu jun , Bai Quan yang , Zhang Ti yin , zheng Teng , Yu Shi yu , Zhang Zhi deng , Lin Su jie , Zhong Bo xiong , Yu Dao jin 
Published: May 2018

AbstractSalmonellaspp. is a high-risk bacterial pathogen that is monitored in imported animal-derived feedstuffs.Serratia fonticolais the bacterial species most frequently confused withSalmonellaspp. in traditional identification methods based on biochemical characteristics, which are time-consuming and labor-intensive, and thus unsuitable for daily inspection and quarantine work. In this study, we established a duplex real-time qPCR method withinvA-andgyrB-specific primers and probes corresponding toSalmonellaspp. andS. fonticola. The method could simultaneously detect both pathogens in imported feedstuffs, with a minimum limit of detection forSalmonellaspp. andS. fonticolaof 197 copies/μL and 145 copies/μL, respectively (correlation coefficient R2= 0.999 in both cases). The amplification efficiency forSalmonellaspp. andS. fonticolawas 98.346% and 96.49%, respectively. Detection of clinical samples was consistent with method GB/T 13091-2002, and all 20 artificially contaminated imported feed samples were positively identified. Thus, the developed duplex real-time qPCR assay displays high specificity and sensitivity, and can be used for the rapid and accurate detection of genomic DNA fromSalmonellaspp. andS. fonticolawithin hours. This represents a significant improvement in the efficiency of detection of both pathogens in imported feedstuffs.ImportanceImported feedstuffs must be tested for pathogenicSalmonellaspecies that represent a biological hazard. Variousnon-Salmonellacolony-forming species belong toEnterobacteriaceae,andSerratia fonticolaforms colonies of similar color and morphology toSalmonellaspp., leading to confusion in daily quarantine tests. Traditional methods based on biochemical and serological characteristics are cumbersome and labor-intensive, and unable to fully support current quarantine testing demands. Thus, there is an urgent need to develop a rapid and accurate method for the effective identification of these pathogens. The duplex real-time qPCR method established herein can rapidly identifySalmonellaspp. andS. fonticola, and has great potential for application to feed safety and prevention of exterior pathogens.
RNA-antimicrobial peptide LL-37 complexes fuel a TLR- and NET-mediated inflammatory cycle of neutrophil activation in psoriasis
Authors: Herster Franziska , Bittner Zsofia , Dickhöfer Sabine , Eise David , Eigenbrod Tatjana , Knorpp Thomas , Schneiderhan-Marra Nicole , Löffler Markus W. , Kalbacher Hubert , Hartl Dominik , Freund Lukas , Schäkel Knut , Heister Martin , Ghoreschi Kamran , Weber Alexander N.R. 
Published: May 2018

AbstractPsoriasis is an inflammatory autoimmune disease characterized by skin lesions showing strong neutrophil (PMN) infiltration and high levels of the antimicrobial peptide, LL37, but the role of PMNs in this context remains unclear. We here show that primary human PMNs, especially PMNs from psoriasis patients, not only respond via TLR8 to human and bacterial RNA in complexed with LL37 by cytokine-, chemokine- and neutrophil extracellular trap (NET)-release; they also actively release additional RNA and LL37 in response to stimulation by the same complex and both RNA and LL37 were found to be highly abundant in psoriatic skin. Moreover, RNA-LL37-induced NETs propagated PMN activation and could thus fuel a PMN-mediated and self-sustaining inflammatory loop that may represent an unexpected early initiator or amplifying event in psoriasis. Given that TLR inhibitory oligodeoxynucleotides prevented the cytokine production and NETosis of PMNs by RNA-LL37 complexes in vitro, our study also highlights TLR blockade as a potential therapeutic intervention strategy in psoriasis.SummaryHuman and bacterial RNA in complex with LL37 activates neutrophils via TLR8 to release cytokines, chemokines and neutrophil extracellular traps (NETs). NETs and neutrophil-rich areas in psoriatic skin contain RNA and LL37, suggesting RNA-LL37 may fuel a PMN-mediated and self-sustaining inflammatory cycle in psoriasis.
Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition
Authors: Robert-Paganin Julien , Auguin Daniel , Houdusse Anne 
Published: May 2018

Abstract:Hypertrophic cardiomyopathies (HCM) result from distinct single-point mutations in sarcomeric proteins that lead to muscle hypercontractility. While different models account for a pathological increase in the power output, clear understanding of the molecular basis of dysfunction in HCM is the mandatory next step to improve current treatments. An optimized quasi-atomic model of the sequestered state of cardiac myosin coupled to X-ray crystallography and in silico analysis of the mechanical compliance of the lever arm allowed us to perform a systematic study for a large set of HCM mutations. We define different classes of mutations depending on their effects on lever arm compliance, sequestered state stability and motor functions. This work reconciles previous models and explains how distinct HCM mutations can have disparate effects on the motor mechano-chemical parameters and yet lead to the same disease. The framework presented here can guide future investigations aiming at finding HCM treatments.
Planning a future randomized clinical trial based on a network of relevant past trials
Authors: Salanti Georgia , Nikolakopoulou Adriani , Sutton Alex J , Reichenbach Stephan , Trelle Sven , Naci Huseyin , Egger Matthias 
Published: May 2018

ABSTRACTBackground: The important role of network meta-analysis of randomized clinical trials in health technology assessment and guideline development is increasingly recognized. This approach has the potential to obtain conclusive results earlier than with new standalone trials or conventional, pairwise meta-analyses.Methods: Network meta-analyses can also be used to plan future trials. We introduce a four-steps framework to plan a new trial that aims to identify the optimal new design that will update the existing evidence to best serve timely clinical and public health decision making. The new trial designed within this framework does not need to include all competing interventions and comparisons of interest and can contribute direct and indirect evidence to the updated network meta-analysis. We present the method by virtually planning a new trial to compare biologics in rheumatoid arthritis and a new trial to compare two drugs for relapsing-remitting multiple sclerosis.Results: A trial design based on updating the evidence from a network meta-analysis of relevant previous trials may require a considerably smaller sample size to reach the same conclusion compared with a trial designed and analyzed in isolation. Challenges in the approach include the complexity of the methodology and the need for a coherent network meta-analysis of previous trials with little heterogeneity.Conclusions: When used judiciously, conditional trial design could significantly reduce waste in clinical research.
Enhanced inhibition of influenza virus infection by peptide-noble metal nanoparticle conjugates
Authors: Alghrair Zaid K. , Fernig David G. , Ebrahimi Bahram 
Published: May 2018

AbstractInfluenza virus is a major medical and veterinary health concern and causes global pandemics. The peptide ‘FluPep’ is an established inhibitor of influenza virus infectivity in model systems. We have explored the potential for FluPep functionalised noble metal nanoparticle to enhance the antiviral activity of the peptide Flupep and determined their potential for the delivery of FluPep. The FluPep ligand designed here is FluPep extended at its N-terminus with the sequence CVVVTAAA-, to allow its incorporation into a mix matrix ligand shell of a peptidol and an alkanethiol ethyleneglycol comprising 70% H-CVVVTol and 30% HS(CH2)11(ethyleneglycol)4 (both mole/mole). Gold and silver nanoparticles (~10 nm diameter) prepared with up to 5% (mole/mole) FluPep ligand contained in the mixture of mix-matrix peptide ligands remained as stable as the control mix-matrix coated nanoparticles against ligand exchange with dithiothreitol. FluPep ligand was found to inhibit viral plaque formation in canine MDCK cells (IC50 2.1 nM), but was less potent than FluPep itself (IC50 140 pM). FluPep ligand functonalised nanoparticles retained antiviral activity in the plaque assay. Moreover, at low grafting densities (where nanoparticles incorporate ~1 FluPep ligand, the antiviral potency in terms of FluPep ligand concentration was enhanced significantly for gold and silver nanoparticles (IC50 ~8-fold and ~3-fold lower, respectively). At higher grafting density the potency relative to free FluPep ligand concentration decreased. The data demonstrate that conjugation of FluPep to gold and silver nanoparticles enhances its antiviral potency; the antimicrobial activity of silver ions may enable the design of even more potent anti-microbial inhibitors.
Tau monomer encodes strains
Authors: Sharma Apurwa M. , Thomas Talitha L. , Woodard DaNae R. , Kashmer Omar M. , Diamond Marc I. 
Published: May 2018

AbstractTauopathies have diverse presentation, progression, and neuropathology. They are linked to tau prion strains, self-replicating assemblies of unique quaternary conformation. Strains can be propagated indefinitely in cultured cells, and induce unique patterns of transmissible neuropathology upon inoculation into mice. Aggregates from a single strain reproduce only that strain upon re-inoculation into cells or mice. DS9 and DS10 cell lines propagate distinct synthetic strains. Surprisingly, DS9 monomer inoculated into naïve cells encoded an identical “sub-strain,” whereas DS10 monomer encoded multiple sub-strains. Sub-strains produced distinct pathology upon inoculation into a tauopathy mouse model (PS19). Brain-derived tau monomer from an Alzheimer’s brain encoded a single strain. Monomer from a corticobasal degeneration brain encoded three sub-strains in which monomer from each encoded all three upon re-inoculation into cells. Tau monomer thus adopts multiple, stable seed-competent conformations, each of which encodes a limited number of strains. This provides insights into the origins of distinct tauopathies.
Absolute pitch can be learned by some adults
Authors: Van Hedger Stephen C. , Heald Shannon L.M , Nusbaum Howard C. 
Published: May 2018

AbstractAbsolute pitch (AP), the rare ability to name any musical note without the aid of a reference note, is thought to develop in an early critical period of development. Although recent research has shown that adults can improve AP abilities in a single training session, the best learners still did not achieve note classification performance comparable to performance of a genuine AP possessor. Here, we demonstrate that genuine AP levels of performance can be trained in eight weeks for some adults, with the best learner passing all measures of AP ability after training and retaining this knowledge for at least four months after training. Alternative explanations of these positive results, such as improving accuracy through adopting a slower, relative pitch strategy, are not supported based on joint analyses of response time and accuracy. The post-training AP assessments were extensive, totaling 204 notes taken from eight different timbres and spanning over seven octaves. These results clearly demonstrate that explicit perceptual training in some adults can lead to AP performance that is behaviorally indistinguishable from AP that results from childhood development. Implications for theories of AP acquisition are discussed.
Illumina sequencing analysis of the ruminal microbiota in high-yield and low-yield lactating dairy cows
Authors: Tong Jinjin , Zhang Hua , Yang Delian , Xiong Benhai , Jiang Linshu 
Published: May 2018

AbstractIn this study, differences in the ruminal bacterial community between high-yield and low-yield lactating dairy cows fed the same diets were investigated. Sixteen lactating dairy cows with similar parity were divided into two groups based on their milk yield: high-yield (HY) and low-yield (LY) groups. On day 21, rumen content samples were collected, and the microbiota composition was determined using Illumina MiSeq sequencing of the 16S rRNA gene. During the study period, dry matter intake (DMI) and milk yield were measured daily, and milk composition was assessed 3 times per week. The results showed that the milk of the LY group tended to have higher fat (P=0.08), protein (P=0.01) and total solid (P=0.04) contents than that of the HY group, though the HY group had higher ruminal acetate (P=0.05), propionate (P=0.02) and volatile fatty acid (VFA) (P=0.02) concentrations. Principal coordinate analysis indicated significant differences in ruminal bacterial community composition and structure between the HY group and LY group. Overall, Bacteroidetes (HY group: 52.91±3.06%; LY group: 61.88±3.03%) was the predominant phylum, followed by Firmicutes (HY group: 41.10±2.74%; LY group: 32.11±2.97%). The abundances of Ruminococcus 2, Lachnospiraceae and Eubacterium coprostanoligenes were significantly higher in the HY group than in the LY group. In addition, 3 genera—Anaerostipes, Bacteroidales and Anaeroplasma—were identified as biomarker species with the greatest impacts on the ruminal community structure in the LY group. These findings facilitate the understanding of bacterial synthesis within the rumen and reveal an important mechanism underlying differences in milk production in dairy cows.
The Influence of PTH 1-34 on the Osteogenic Characteristics of Adipose and Bone Marrow Derived Stem Cells from Juvenile and Ovarectomized Rats
Authors: Osagie-Clouard Liza , Sanghani-Kerai Anita , Coathup Melanie , Pendegrass catherine , Briggs Timothy , Blunn Gordon 
Published: May 2018

AbstractBackground: Mesenchymal Stem Cells (MSCs) are of growing interest in terms of bone regeneration; the majority of preclinical trials utilise bone marrow derived stem cells (bMSCs), though this is not without isolation and expansion difficultiesObjective: We compare the characteristics of bone marrow and adipose derived cells from juvenile, adult and ovarectomized rats; also assessing the effect of hPTH 1-34, on their osteogenic potential.Methods: cells were isolated from the adipose and bone marrow of juvenile, adult and previously ovarectomized wistar rats. Cells were characterised with flowcytometery, proliferation assays, osteogenic and adipogenic differentiation, and migration to SDF-1. Experiments were repeated with and without co-culturing with 50nMol of intermittent PTH 1-34.Results: The juvenile and adult MSCs demonstrated significantly increased differentiation into bone and fat and superior migration towards SDF-1 than ovarectomized groups, this was the case for adipose and bone marrow derived cells equally. PTH increased parameters of osteogenic differentiation and migration to SDF-1, this was significant for all cell types, though had the most significant effect on cells derived from OVX animals. Bone marrow derived cells from all groups, showed increased mineralisation and migration to SDF-1 compared to adipose derived cells.Conclusion: Juvenile MSCs showed significantly greater migration to SDF-1 and showed greater osteogenic and adipogenic differentiation compared to cells from osteopenic rats, this was true for bone marrow and adipose derived cells. The addition of PTH, increased the osteogenic characteristics and migration of all cells, and further illustrates the possible clinical utility of both PTH and MSCs from various sources in bone regenerative therapies
First natural crossover recombination of intact ORFs between two distinct species of the familyClosteroviridae
Authors: Ruiz Leticia , Simón Almudena , García Carmen , Velasco Leonardo , Janssen Dirk 
Published: May 2018

AbstractLettuce chlorosis virus-SP (LCV-SP) (familyClosteroviridae, genusCrinivirus), is a new strain of LCV which is able to infect green bean plants and incapable of infecting lettuce crops. In the present study, high throughput and Sanger sequencing of RNA was used to obtain the LCV-SP full-length sequence. The LCV-SP genome comprises 8825 nt and 8672 nt equivalent with RNA1 and RNA2 respectively. RNA1 of LCV-SP contains four ORFs, the proteins encoded by the ORF1a and ORF1b are closely related to LCV RNA1 from California (FJ380118) whereas the 3´ end encodes proteins which share high amino acid sequence identity with RNA1 of BnYDV (EU191904). The genomic sequence of RNA2 consists of 8 ORFs, instead of 10 ORFs contained in LCV-California isolate. The distribution of vsiRNA (virus-derived small interfering RNA) along the LCV-SP genome suggested the presence of subgenomic RNAs corresponding with HSP70, P6.4 and P60. Results of the analysis using RDP4 and Simplot programs are the proof of the evidence that LCV-SP is the first recombinant of the familyClosteroviridaeby crossover recombination of intact ORFs, being the LCV RNA1 (FJ380118) and BnYDV RNA1 (EU191904) the origin of the new LCV strain. Genetic diversity values of virus isolates in the recombinant region obtained after sampling LCV-SP infected green bean between 2011 and 2017 might suggest that the recombinant virus event occurred in the area before this period. The presence of LCV-SP shows the role of recombination as a driving force of evolution within the genusCrinivirus, a globally distributed, emergent genus.