bluuebunny/crossref_metadata_2025_split huggingface dataset:
A transcriptome-wide association study identifies PALMD as a susceptibility gene for calcific aortic valve stenosis
Authors: Thériault Sébastien , Gaudreault Nathalie , Lamontagne Maxime , Rosa Mickael , Boulanger Marie-Chloé , Messika-Zeitoun David , Clavel Marie-Annick , Capoulade Romain , Dagenais François , Pibarot Philippe , Mathieu Patrick , Bossé Yohan 
Published: March 2018

AbstractCalcific aortic valve stenosis (CAVS) is a common and life-threatening heart disease and the current treatment options cannot stop or delay its progression. A GWAS on 1009 cases and 1017 ethnically matched controls was combined with a large-scale eQTL mapping study of human aortic valve tissues (n = 233) to identify susceptibility genes for CAVS. Replication was performed in the UK Biobank, including 1391 cases and 352,195 controls. A transcriptome-wide association study (TWAS) reveals PALMD (palmdelphin) as significantly associated with CAVS. The CAVS risk alleles and increasing disease severity are both associated with decreased mRNA expression levels of PALMD in valve tissues. The top variant identified shows a similar effect and strong association with CAVS (P = 1.53 × 10−10) in UK Biobank. The identification of PALMD as a susceptibility gene for CAVS provides insights into the genetic nature of this disease, opens avenues to investigate its etiology and to develop much-needed therapeutic options.
Flexibility in motor timing constrains the topology and dynamics of pattern generator circuits
Authors: Pehlevan Cengiz , Ali Farhan , Ölveczky Bence P. 
Published: March 2018

AbstractTemporally precise movement patterns underlie many motor skills and innate actions, yet the flexibility with which the timing of such stereotyped behaviors can be modified is poorly understood. To probe this, we induce adaptive changes to the temporal structure of birdsong. We find that the duration of specific song segments can be modified without affecting the timing in other parts of the song. We derive formal prescriptions for how neural networks can implement such flexible motor timing. We find that randomly connected recurrent networks, a common approximation for how neocortex is wired, do not generally conform to these, though certain implementations can approximate them. We show that feedforward networks, by virtue of their one-to-one mapping between network activity and time, are better suited. Our study provides general prescriptions for pattern generator networks that implement flexible motor timing, an important aspect of many motor skills, including birdsong and human speech.
Enumeration, functional responses and cytotoxic capacity of MAIT cells in newly diagnosed and relapsed multiple myeloma
Authors: Gherardin Nicholas A. , Loh Liyen , Admojo Lorenztino , Davenport Alexander J. , Richardson Kelden , Rogers Amy , Darcy Phillip K. , Jenkins Misty R. , Prince H. Miles , Harrison Simon J. , Quach Hang , Fairlie David P. , Kedzierska Katherine , McCluskey James , Uldrich Adam P. , Neeson Paul J. , Ritchie David S. , Godfrey Dale I. 
Published: March 2018

AbstractMucosal-associated invariant T (MAIT) cells are T cells that recognise vitamin-B derivative Ag presented by the MHC-related-protein 1 (MR1) antigen-presenting molecule. While MAIT cells are highly abundant in humans, their role in tumour immunity remains unknown. Here we have analysed the frequency and function of MAIT cells in multiple myeloma (MM) patients. We show that MAIT cell frequency in blood is reduced compared to healthy adult donors, but comparable to elderly healthy control donors. Furthermore, there was no evidence that MAIT cells accumulated at the disease site (bone marrow) of these patients. Newly diagnosed MM patient MAIT cells had reduced IFNγ production and CD27 expression, suggesting an exhausted phenotype, although IFNγ-producing capacity is restored in relapsed/refractory patient samples. Moreover, immunomodulatory drugs Lenalidomide and Pomalidomide, indirectly inhibited MAIT cell activation. We further show that cell lines can be pulsed with vitamin-B derivative Ags and that these can be presented via MR1 to MAIT cells in vitro, to induce cytotoxic activity comparable to that of natural killer (NK) cells. Thus, MAIT cells are reduced in MM patients, which may contribute to disease in these individuals, and moreover, MAIT cells may represent new immunotherapeutic targets for treatment of MM and other malignancies.
Species replacement dominates megabenthos beta diversity in a remote seamount setting
Authors: Victorero Lissette , Robert Katleen , Robinson Laura F. , Taylor Michelle L. , Huvenne Veerle A. I. 
Published: March 2018

AbstractSeamounts are proposed to be hotspots of deep-sea biodiversity, a pattern potentially arising from increased productivity in a heterogeneous landscape leading to either high species co-existence or species turnover (beta diversity). However, studies on individual seamounts remain rare, hindering our understanding of the underlying causes of local changes in beta diversity. Here, we investigated processes behind beta diversity using ROV video, coupled with oceanographic and quantitative terrain parameters, over a depth gradient in Annan Seamount, Equatorial Atlantic. By applying recently developed beta diversity analyses, we identified ecologically unique sites and distinguished between two beta diversity processes: species replacement and changes in species richness. The total beta diversity was high with an index of 0.92 out of 1 and was dominated by species replacement (68%). Species replacement was affected by depth-related variables, including temperature and water mass in addition to the aspect and local elevation of the seabed. In contrast, changes in species richness component were affected only by the water mass. Water mass, along with substrate also affected differences in species abundance. This study identified, for the first time on seamount megabenthos, the different beta diversity components and drivers, which can contribute towards understanding and protecting regional deep-sea biodiversity.
In silico screening for human norovirus antivirals reveals a novel non-nucleoside inhibitor of the viral polymerase
Authors: Ferla Salvatore , Netzler Natalie E. , Ferla Sebastiano , Veronese Sofia , Tuipulotu Daniel Enosi , Guccione Salvatore , Brancale Andrea , White Peter A. , Bassetto Marcella 
Published: March 2018

AbstractHuman norovirus causes approximately 219,000 deaths annually, yet there are currently no antivirals available. A virtual screening of commercially available drug-like compounds (~300,000) was performed on the suramin and PPNDS binding-sites of the norovirus RNA-dependent RNA polymerase (RdRp). Selected compounds (n = 62) were examined for inhibition of norovirus RdRp activity using an in vitro transcription assay. Eight candidates demonstrated RdRp inhibition (>25% inhibition at 10 µM), which was confirmed using a gel-shift RdRp assay for two of them. The two molecules were identified as initial hits and selected for structure-activity relationship studies, which resulted in the synthesis of novel compounds that were examined for inhibitory activity. Five compounds inhibited human norovirus RdRp activity (>50% at 10 µM), with the best candidate, 54, demonstrating an IC50 of 5.6 µM against the RdRp and a CC50 of 62.8 µM. Combinational treatment of 54 and the known RdRp site-B inhibitor PPNDS revealed antagonism, indicating that 54 binds in the same binding pocket. Two RdRps with mutations (Q414A and R419A) previously shown to be critical for the binding of site-B compounds had no effect on inhibition, suggesting 54 interacts with distinct site-B residues. This study revealed the novel scaffold 54 for further development as a norovirus antiviral.
Probe-caught spontaneous and deliberate mind wandering in relation to self-reported inattentive, hyperactive and impulsive traits in adults
Authors: Arabacı Gizem , Parris Benjamin A. 
Published: March 2018

AbstractResearch has revealed a positive relationship between types of mind wandering and ADHD at clinical and subclinical levels. However, this work did not consider the relationship between mind wandering and the core symptoms of ADHD: inattention, hyperactivity and impulsivity. Given that the DMS-V attributes mind wandering to inattention only, and that only inattention is thought to result from impairment to the executive function linked to mind wandering, the present research sought to examine this relationship in 80 undiagnosed adults. Using both standard and easy versions of the Sustained Attention to Response Task (SART) we measured both spontaneous and deliberate mind wandering. We found that spontaneous mind wandering was related to self-reported inattentive traits when the task was cognitively more challenging (standard SART). However, hyperactive and impulsive traits were related to spontaneous mind wandering independent of task difficulty. The results suggest inattentive traits are not uniquely related to mind wandering; indeed, adults with hyperactive/impulsive traits were more likely to experience mind wandering, suggesting that mind wandering might not be useful diagnostic criteria for inattention.
Long-term regeneration and remodeling of the pig esophagus after circumferential resection using a retrievable synthetic scaffold carrying autologous cells
Authors: La Francesca Saverio , Aho Johnathon M. , Barron Matthew R. , Blanco Ellen W. , Soliman Sherif , Kalenjian Lena , Hanson Ariel D. , Todorova Elisaveta , Marsh Matthew , Burnette KaLia , DerSimonian Harout , Odze Robert D. , Wigle Dennis A. 
Published: March 2018

AbstractTreatment of esophageal disease can necessitate resection and reconstruction of the esophagus. Current reconstruction approaches are limited to utilization of an autologous conduit such as stomach, small bowel, or colon. A tissue engineered construct providing an alternative for esophageal replacement in circumferential, full thickness resection would have significant clinical applications. In the current study, we demonstrate that regeneration of esophageal tissue is feasible and reproducible in a large animal model using synthetic polyurethane electro-spun grafts seeded with autologous adipose-derived mesenchymal stem cells (aMSCs) and a disposable bioreactor. The scaffolds were not incorporated into the regrown esophageal tissue and were retrieved endoscopically. Animals underwent adipose tissue biopsy to harvest and expand autologous aMSCs for seeding on electro-spun polyurethane conduits in a bioreactor. Anesthetized pigs underwent full thickness circumferential resection of the mid-lower thoracic esophagus followed by implantation of the cell seeded scaffold. Results from these animals showed gradual structural regrowth of endogenous esophageal tissue, including squamous esophageal mucosa, submucosa, and smooth muscle layers with blood vessel formation. Scaffolds carrying autologous adipose-derived mesenchymal stem cells may provide an alternative to the use of a gastro-intestinal conduit for some patients following resection of the esophagus.
Biogeographic patterns of aerobic anoxygenic phototrophic bacteria reveal an ecological consistency of phylogenetic clades in different oceanic biomes
Authors: Lehours Anne-Catherine , Enault François , Boeuf Dominique , Jeanthon Christian 
Published: March 2018

AbstractIn marine environments, aerobic anoxygenic phototrophic (AAP) bacterial assemblages vary in space and along environmental gradients but the factors shaping their diversity and distribution at different taxonomic levels remain poorly identified. Using sets of sequences encoding the M sub-unit of the photosynthetic apparatus from different oceanic regions, we prioritized the processes underlying AAP bacterial biogeographical patterns. The present analysis offers novel insights into the ecological distribution of marine AAP bacteria and highlights that physiological constraints play a key role in structuring AAP bacterial assemblages at a global scale. Salinity especially seems to favor lineage-specific adaptations. Moreover, by inferring the evolutionary history of habitat transitions, a substantial congruence between habitat and evolutionary relatedness was highlighted. The identification of ecological cohesive clades for AAP bacteria suggests that prediction of AAP bacterial assemblages is possible from marine habitat properties.
DNA damage induces a SAMHD1-mediated block to the infection of macrophages by HIV-1
Authors: Jáuregui Paula , Landau Nathaniel R. 
Published: March 2018

AbstractMonocyte-derived macrophages (MDMs) are an important target for HIV-1 despite SAMHD1, a myeloid restriction factor for which HIV-1 lacks a counteracting accessory protein. The antiviral activity of SAMHD1 is modulated by phosphorylation of T592 by cyclin-dependent kinases (CDK). We show that treatment of MDMs with neocarzinostatin, a compound that introduces double strand breaks (DBS) in genomic DNA, results in the decrease of phosphorylated SAMHD1, activating its antiviral activity and blocking HIV-1 infection. The effect was specific for DSB as DNA damage induced by UV light irradiation did not affect SAMHD1 phosphorylation and did not block infection. The block to infection was at reverse transcription and was counteracted by Vpx, demonstrating that it was caused by SAMHD1. Neocarzinostatin treatment also activated an innate immune response that induced interferon-stimulated genes but this was not involved in the block to HIV-1 infection, as it was not relieved by an interferon-blocking antibody. In response to Neocarzinostatin-induced DNA damage, the level of the CDK inhibitor p21cip1 increased which could account for the decrease of phosphorylated SAMHD1. The results show that the susceptibility of MDMs to HIV-1 infection can be affected by stimuli that alter the phosphorylation state of SAMHD1, one of which is the DNA damage response.
Mechanistic insights of Li+ diffusion within doped LiFePO4 from Muon Spectroscopy
Authors: Johnson Ian D. , Ashton Thomas E. , Blagovidova Ekaterina , Smales Glen J. , Lübke Mechthild , Baker Peter J. , Corr Serena A. , Darr Jawwad A. 
Published: March 2018

AbstractThe Li+ ion diffusion characteristics of V- and Nb-doped LiFePO4 were examined with respect to undoped LiFePO4 using muon spectroscopy (µSR) as a local probe. As little difference in diffusion coefficient between the pure and doped samples was observed, offering DLi values in the range 1.8–2.3 × 10−10 cm2 s−1, this implied the improvement in electrochemical performance observed within doped LiFePO4 was not a result of increased local Li+ diffusion. This unexpected observation was made possible with the µSR technique, which can measure Li+ self-diffusion within LiFePO4, and therefore negated the effect of the LiFePO4 two-phase delithiation mechanism, which has previously prevented accurate Li+ diffusion comparison between the doped and undoped materials. Therefore, the authors suggest that µSR is an excellent technique for analysing materials on a local scale to elucidate the effects of dopants on solid-state diffusion behaviour.
Detailed ecological associations of triatomines revealed by metabarcoding and next-generation sequencing: implications for triatomine behavior and Trypanosoma cruzi transmission cycles
Authors: Dumonteil Eric , Ramirez-Sierra Maria-Jesus , Pérez-Carrillo Silvia , Teh-Poot Christian , Herrera Claudia , Gourbière Sébastien , Waleckx Etienne 
Published: March 2018

AbstractTrypanosoma cruzi is the agent of Chagas disease, transmitted by hematophagous triatomine vectors. Establishing transmission cycles is key to understand the epidemiology of the disease, but integrative assessments of ecological interactions shaping parasite transmission are still limited. Current approaches also lack sensitivity to assess the full extent of this ecological diversity. Here we developed a metabarcoding approach based on next-generation sequencing to identify triatomine gut microbiome, vertebrate feeding hosts, and parasite diversity and their potential interactions. We detected a dynamic microbiome in Triatoma dimidiata, including 23 bacterial orders, which differed according to blood sources. Fourteen vertebrate species served as blood sources, corresponding to domestic, synantropic and sylvatic species, although four (human, dog, cow and mice) accounted for over 50% of blood sources. Importantly, bugs fed on multiple hosts, with up to 11 hosts identified per bug, indicating very frequent host-switching. A high clonal diversity of T. cruzi was detected, with up to 20 haplotypes per bug. This analysis provided much greater sensitivity to detect multiple blood meals and multiclonal infections with T. cruzi, which should be taken into account to develop transmission networks, and characterize the risk for human infection, eventually leading to a better control of disease transmission.
Sex differentials in relationships between functional fitness and cognitive performance in older adults: a canonical correlation analysis
Authors: Guo Yan , Yang Mei , Yan Yaqiong , Wang Liang , Gong Jie 
Published: March 2018

AbstractThis study aimed to explore the sex differentials in correlations between functional fitness (FF) and cognitive impairment (CI) in older adults without dementia. A community-based cross-sectional study was conducted using 2096 adults more than 65 years of age. The Senior Fitness test and Mini-mental State Examination (MMSE) were used to measure FF and cognitive performance. Canonical correlation analysis (CCA) was performed to evaluate the relationships between FF and MMSE. Our results confirmed the relationships between FF and CI, furthermore FF and MMSE were significantly different between men and women (P < 0.05). CCA results showed overall FF was positively correlated with overall MMSE in both men (canonical coefficient = 0.37, P < 0.0001) and women (first canonical coefficient = 0.42, P < 0.0001; second canonical coefficient = 0.17, P = 0.004). Among men, 30s-arm curl and language were most highly correlated with FF and MMSE, respectively. Whereas among women, 30s-arm curl and eight-foot up-and-go were most highly correlated with FF, and orientation and recall were most highly correlated with MMSE. In conclusion, there was a sex difference in the relationships between FF and MMSE, which facilitated generating insight into cognitive performance improvement from the perspective of FF enhancement by sex. Prospective studies are needed to explore the causality between FF and cognitive performance.
Results of the national organised colorectal cancer screening program with FIT in Paris
Authors: Pellat Anna , Deyra Jacques , Coriat Romain , Chaussade Stanislas 
Published: March 2018

AbstractIn France, colorectal cancer (CRC) benefits from a nationwide screening program. The faecal immunochemical test (FIT) is being used since April 2015. The test is recommended in asymptomatic patients followed by a colonoscopy if positive for identification and treatment of colorectal lesions. We investigate the CRC national organised screening program using FIT in Paris. We performed a retrospective observational study, collecting data from the screening program in Paris using the ADECA75 database. Rates of participation, numbers of positive FIT, detection rates and positive predictive values (PPV) for advanced adenomas (AA) and/or CRC were determined. Between 01/01/2016 and 30/06/2017, 620.227 Parisians were eligible and 409.340 were invited to participate to the program. A total of 88.796 participants (23%) performed the test with 3.839 positive tests (4.3%). In the positive test population, 2.706 out of 3.839 individuals (70.5%) performed the required colonoscopy with available reports. Histology reports were only available for 2.401 participants (88,7%). Regarding lesions, 733 (30,5%) and 205 patients (8.5%) had AA and CRC, respectively. Over 18 months of screening with FIT in Paris, the PPV is in line with expected results while the participation rate is below European recommendations.
Emergence of Different Recombinant Porcine Reproductive and Respiratory Syndrome Viruses, China
Authors: Liu Yanyan , Li Jianda , Yang Jie , Zeng Hao , Guo Lihui , Ren Sufang , Sun Wenbo , Chen Zhi , Cong Xiaoyan , Shi Jianli , Chen Lei , Du Yijun , Li Jun , Wang Jinbao , Wu Jiaqiang , Yu Jiang 
Published: March 2018

AbstractEpidemiological investigations were conducted on recently emerging porcine reproductive and respiratory syndrome virus (PRRSV) strains in Shandong province in 2014–2015. The proportion of the NADC30 strain identified by ORF7 sequence alignment has been gradually increasing. Three emerging PRRSV strains were successfully isolated, and the complete genomic sequences were determined. Our results indicate the importance of recombinant strains in Shandong province, China. There was a varied degree of recombination of two or three strains (classical, HP-PRRSV and/or NADC30). Moreover, the recombination strains affected the pathogenicity of newly emerged strains.
Mechanism of the Escherichia coli MltE lytic transglycosylase, the cell-wall-penetrating enzyme for Type VI secretion system assembly
Authors: Byun Byungjin , Mahasenan Kiran V. , Dik David A. , Marous Daniel R. , Speri Enrico , Kumarasiri Malika , Fisher Jed F. , Hermoso Juan A. , Mobashery Shahriar 
Published: March 2018

AbstractLytic transglycosylases (LTs) catalyze the non-hydrolytic cleavage of the bacterial cell wall by an intramolecular transacetalization reaction. This reaction is critically and broadly important in modifications of the bacterial cell wall in the course of its biosynthesis, recycling, manifestation of virulence, insertion of structural entities such as the flagellum and the pili, among others. The first QM/MM analysis of the mechanism of reaction of an LT, that for the Escherichia coli MltE, is undertaken. The study reveals a conformational itinerary consistent with an oxocarbenium-like transition state, characterized by a pivotal role for the active-site glutamic acid in proton transfer. Notably, an oxazolinium intermediate, as a potential intermediate, is absent. Rather, substrate-assisted catalysis is observed through a favorable dipole provided by the N-acetyl carbonyl group of MurNAc saccharide. This interaction stabilizes the incipient positive charge development in the transition state. This mechanism coincides with near-synchronous acetal cleavage and acetal formation.
Cortactin regulates endo-lysosomal sorting of AMPARs via direct interaction with GluA2 subunit
Authors: Parkinson Gabrielle T. , Chamberlain Sophie E. L. , Jaafari Nadia , Turvey Matthew , Mellor Jack R. , Hanley Jonathan G. 
Published: March 2018

AbstractAMPA receptor (AMPAR) trafficking is a key determinant of synaptic strength and synaptic plasticity. Under basal conditions, constitutive trafficking maintains surface AMPARs by internalization into the endosomal system, where the majority are sorted and targeted for recycling back to the plasma membrane. NMDA receptor (NMDAR)-dependent Long-Term Depression (LTD) is characterised by a reduction in synaptic strength, and involves endosomal sorting of AMPARs away from recycling pathways to lysosomes. The mechanisms that determine whether AMPARs are trafficked to lysosomes or to recycling endosomes, especially in response to NMDAR stimulation, are unclear. Here, we define a role for the actin-regulatory protein cortactin as a mediator of AMPAR endosomal sorting by direct interaction with the GluA2 subunit. Disrupting GluA2-cortactin binding in neurons causes the targeting of GluA2/A3-containing receptors to lysosomes and their consequent degradation, resulting in a loss of surface and synaptic GluA2 under basal conditions and an occlusion of subsequent LTD expression. Furthermore, we show that NMDAR stimulation causes a dissociation of endogenous cortactin from GluA2 via tyrosine phosphorylation of cortactin. These results demonstrate that cortactin maintains GluA2/A3 levels by directing receptors away from lysosomes, and that disrupting GluA2-cortactin interactions to target GluA2/A3 to lysosomes is an essential component of LTD expression.