bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and Effectiveness of Fingolimod in Real-World Multiple Sclerosis Portuguese Patients
Authors: Ribeiro de Barros Ariana Helena , Fiadeiro Sequeira João Paulo , Lopes de Sousa Ary Severino , Cheganças Capela Carlos Miguel , Gomes Pedrosa Rui Manuel , dos Santos Manita Manuel Alexandre 
Published: June 2018

Objectives
The aim of this study was to evaluate postmarketing fingolimod safety and effectiveness in a real-world clinical population.

Methods
This was a retrospective, single-center study with active multiple sclerosis patients treated with fingolimod with at least 12 months of follow-up. Demographic and clinical and imaging characteristics, including annualized relapse rate (ARR), Expanded Disability Status Score, previous treatment, adverse events, treatment duration, and reason for discontinuation, were analyzed.

Results
Sixty-three patients were included; 61.9% were females. Mean age and mean disease duration were 30.9 ± 9.3 years and 11.4 ± 6.9 years, respectively. Fifty-one patients received prior first-line disease-modifying therapies, 11 patients were previously treated with natalizumab, and 1 was treatment naive. The ARR decreased by 75.3% for the total population at the end of the first year of treatment (P < 0.0001). The proportion of relapse-free patients improved significantly. All patients previously treated with natalizumab switched because of safety concerns, although the ARR kept low after treatment initiation. Only 3 patients (4.8%) discontinued treatment because of adverse drug reactions, and 2 (3.2%) because of lack of effectiveness.

Conclusions
In this real-world audit, fingolimod appeared to be effective after first-line treatment failure in reducing disease activity and progression of disability throughout the observational period and may be an effective option after natalizumab. Fingolimod was well tolerated with low rates of discontinuation and adverse events.
Defining Inflammatory Cell States in Rheumatoid Arthritis Joint Synovial Tissues by Integrating Single-cell Transcriptomics and Mass Cytometry
Authors: Zhang Fan , Wei Kevin , Slowikowski Kamil , Fonseka Chamith Y. , Rao Deepak A. , Kelly Stephen , Goodman Susan M. , Tabechian Darren , Hughes Laura B. , Salomon-Escoto Karen , Watts Gerald F. M. , Apruzzese William , Lieb David J. , Boyle David L. , Mandelin Arthur M. ,   Accelerating Medicines Partnership: RA Phase 1, AMP RA/SLE, Boyce Brendan F. , DiCarlo Edward , Gravallese Ellen M. , Gregersen Peter K. , Moreland Larry , Firestein Gary S. , Hacohen Nir , Nusbaum Chad , Lederer James A. , Perlman Harris , Pitzalis Costantino , Filer Andrew , Holers V. Michael , Bykerk Vivian P. , Donlin Laura T. , Anolik Jennifer H. , Brenner Michael B. , Raychaudhuri Soumya 
Published: June 2018

AbstractTo define the cell populations in rheumatoid arthritis (RA) driving joint inflammation, we applied single-cell RNA-seq (scRNA-seq), mass cytometry, bulk RNA-seq, and flow cytometry to sorted T cells, B cells, monocytes, and fibroblasts from 51 synovial tissue RA and osteoarthritis (OA) patient samples. Utilizing an integrated computational strategy based on canonical correlation analysis to 5,452 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics together revealed cell states expanded in RA synovia: THY1+HLAhigh sublining fibroblasts (OR=33.8), IL1B+ pro-inflammatory monocytes (OR=7.8), CD11c+T-bet+ autoimmune-associated B cells (OR=5.7), and PD-1+Tph/Tfh (OR=3.0). We also defined CD8+ T cell subsets characterized by GZMK+, GZMB+, and GNLY+ expression. Using bulk and single-cell data, we mapped inflammatory mediators to source cell populations, for example attributing IL6 production to THY1+HLAhigh fibroblasts and naïve B cells, and IL1B to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.
Automatic vegetation identification in Google Earth images using a convolutional neural network: A case study for Japanese bamboo forests
Authors: Watanabe Shuntaro , Sumi Kazuaki , Ise Takeshi 
Published: June 2018

ABSTRACTClassifying and mapping vegetation are very important tasks in environmental science and natural resource management. However, these tasks are not easy because conventional methods such as field surveys are highly labor intensive. Automatic identification of target objects from visual data is one of the most promising ways to reduce the costs for vegetation mapping. Although deep learning has become a new solution for image recognition and classification recently, in general, detection of ambiguous objects such as vegetation still is considered difficult. In this paper, we investigated the potential for adapting the chopped picture method, a recently described protocol for deep learning, to detect plant communities in Google Earth images. We selected bamboo forests as the target. We obtained Google Earth images from three regions in Japan. By applying the deep convolutional neural network, the model successfully learned the features of bamboo forests in Google Earth images, and the best trained model correctly detected 97% of the targets. Our results show that identification accuracy strongly depends on the image resolution and the quality of training data. Our results also highlight that deep learning and the chopped picture method can potentially become a powerful tool for high accuracy automated detection and mapping of vegetation.
Potential impacts of transport infrastructure and traffic on bird conservation in Swedish Special Protection Areas
Authors: Helldin Jan Olof 
Published: June 2018

AbstractThe ecological impacts of roads and railways extend into the surrounding landscape, leading to habitat degradation and reduced animal densities within an area that is considerably larger than the actual road or railway corridor. For birds, an extensive meta-analysis has pointed at an average of 20% density reduction within 1 km from the infrastructure. I investigated to what extent this density reduction could potentially compromise the habitat quality and conservation value of Swedish Natura 2000 areas designated for the protection of birds (Special Protection Areas; SPAs). A majority (63%) of Swedish SPAs are at least to some extent found within this 1 km potential effect zone. The total overlap between SPA and effect zone is 126,000 ha, or 4.2% of the country’s SPA area. There are however large differences among biogeographical regions. In the southern (continental) and coastal regions combined, 25.8% of the total SPA area fall within the effect zone, representing an estimated 4-7% reduction in bird abundance within SPAs. The probability of overlap with effect zone is higher for larger SPAs. However, the proportion of overlap is higher for smaller SPAs, and accordingly smaller sites can be assumed to experience a greater impact from transport infrastructure and traffic. The impacts on Natura 2000 sites are particularly concerning as this network of protected areas is a cornerstone to maintain and restore biodiversity within EU. I recommend putting a stronger emphasis in the management of Natura 2000 sites on the potential threats to wildlife conservation caused by transport infrastructure and traffic. Special attention should be paid in sites with a large overlap with the effect zone, and in sites hosting particularly vulnerable taxa or habitats. Infrastructure owners and managers should do their best to minimize and compensate for the negative impacts of roads and railways and related traffic in SPAs and other protected areas.
Epigenetic analysis identifies factors driving racial disparity in prostate cancer
Authors: Rai Richa , Yadav Shalini S , Pan Heng , O’Connor James , Alshalalfa Mohamed , Davicioni Elai , Taioli Emanuela , Elemento Olivier , Tewari Ashutosh K , Yadav Kamlesh K 
Published: June 2018

AbstractProstate cancer (PCa) is the second most leading cause of death in men worldwide. African American men (AA) represent more aggressive form of PCa as compared to Caucasian (CA) counterparts. Evidence suggests that genetic and other biological factors could account for the observed racial disparity. We analyzed the cancer genome atlas (TCGA) dataset (2015) for existing epigenetic variation in AA and CA prostate cancer patients, and carried out Reduced Representation Bisulphite Sequencing (RRBS) analysis to identify global methylation changes in AA and CA prostate cancer patients. The TCGA dataset analysis revealed that the epigenetic heterogeneity could be categorized into 4 classes, where AA associated primarily to methylation cluster 1 (p value 0.048), and CA associated to methylation cluster 3 (p value 0.000146). We identified enrichment of Wnt signaling genes in both AA and CA, however they were differentially activated in terms of canonical and non-canonical Wnt signaling pathway activation. This was further validated using the GenomeDx expression data. Our RRBS data also suggested distinct methylation patterns in AA compared to CA, and in part validated our TCGA findings. Survival analysis using the RRBS data suggested hypomethylated genes to be significantly associated with recurrence of prostate cancer in CA (p=6.07×10−6) as well as in AA (p=0.0077). Overall, the observed racial disparity in the molecular mechanism involved in the pathogenesis of prostate cancer suggests diverse heterogeneity that potentially could affect survival and should be considered during prognosis and treatment.
Brain Connectivity Tracks Effects of Chemotherapy Separately from Behavioral Measures
Authors: Kardan Omid , Askren Mary K. , Jung Misook , Peltier Scott , Misic Bratislav , Churchill Nathan W. , Reuter-Lorenz Patricia A. , Cimprich Bernadine , Berman Marc G. 
Published: June 2018

AbstractSeveral studies in cancer research have suggested that cognitive dysfunction following chemotherapy, referred to in lay terms as “chemobrain”, is a serious problem. At present, the changes in integrative brain function that underlie such dysfunction remains poorly understood. Recent developments in neuroimaging suggest that patterns of functional connectivity can provide a broadly applicable neuromarker of cognitive performance and other psychometric measures. The current study used multivariate analysis methods to identify patterns of disruption in resting state functional connectivity of the brain due to chemotherapy and the degree to which the disruptions can be linked to behavioral measures of distress and cognitive performance. Sixty two women (22 healthy control, 18 patients treated with adjuvant chemotherapy, and 22 treated without chemotherapy) were evaluated with neurocognitive measures followed by self-report questionnaires and open eyes resting-state fMRI scanning at three time points: diagnosis (M0, pre-adjuvant treatment), at least 1 month (M1), and 7 months (M7) after treatment. The results indicated deficits in cognitive health of breast cancer patients immediately after chemotherapy that improved over time. This psychological trajectory was paralleled by a disruption and later recovery of resting-state functional connectivity, mostly in the parietal and frontal brain regions. The functional connectivity alteration pattern seems to be a separable treatment symptom from the decreased cognitive health. More targeted support for patients should be developed to ameliorate these multi-faceted side effects of chemotherapy treatment on neural functioning and cognitive health.
Fbxo2VHCmouse and embryonic stem cell reporter lines delineatein vitro-generated inner ear sensory epithelia cells and enable otic lineage selection and Cre-recombination
Authors: Hartman Byron H. , Böscke Robert , Ellwanger Daniel C. , Keymeulen Sawa , Scheibinger Mirko , Heller Stefan 
Published: June 2018

ABSTRACTWhile the mouse has been a productive model for inner ear studies, the lack of highly specific genes and tools have presented challenges, specifically forin vitrostudies of otic development, where innate cellular heterogeneity and disorganization increase the reliance on lineage-specific markers. To address this challenge in mice and embryonic stem (ES) cells, we targeted the lineage-specific otic geneFbxo2with a multicistronic reporter cassette (Venus/Hygro/CreER = VHC). In otic organoids derived from ES cells,Fbxo2VHCspecifically delineates otic progenitors and inner ear sensory epithelia. In mice, Venus expression and CreER activity reveal a cochlear developmental gradient, label the prosensory lineage, show enrichment in a subset of type I vestibular hair cells, and expose strong expression in adult cerebellar granule cells. We provide a toolbox of multiple spectrally distinct reporter combinations to the community for studies that require use of fluorescent reporters, hygromycin selection, and conditional Cre-mediated recombination.SUMMARY STATEMENTA multifunctionalFbxo2-targeted reporter in mice and stem cells was developed and characterized as a resource for inner ear studies, along with a toolbox of plasmids to facilitate the use of this technique for other users.
Endolysosomal degradation of Tau and its role in glucocorticoid-driven hippocampal malfunction
Authors: Vaz-Silva João , Zhu Mei , Jin Qi , Zhuravleva Viktoriya , Gomes Patrícia , Quintremil Sebastian , Meira Torcato , Silva Joana , Dioli Chrysoula , Soares-Cunha Carina , Daskalakis Nikolaos P. , Sousa Nuno , Sotiropoulos Ioannis , Waites Clarissa L 
Published: June 2018

AbstractEmerging studies implicate Tau as an essential mediator of neuronal atrophy and cognitive impairment in Alzheimer’s disease (AD), yet the factors that precipitate Tau dysfunction in AD are poorly understood. Chronic environmental stress and elevated glucocorticoids (GC), the major stress hormones, are associated with increased risk of AD, and have been shown to trigger intracellular Tau accumulation and downstream Tau-dependent neuronal dysfunction. However, the mechanisms through which stress and GC disrupt Tau clearance and degradation in neurons remain unclear. Here, we demonstrate that Tau undergoes degradation via endolysosomal sorting in a pathway requiring the small GTPase Rab35 and the endosomal sorting complex required for transport (ESCRT) machinery. Furthermore, we find that GC impair Tau degradation by decreasing Rab35 levels, and that AAV-mediated expression of Rab35 in the hippocampus rescues GC-induced Tau accumulation and related neurostructural deficits. These studies indicate that the Rab35/ESCRT pathway is essential for Tau clearance and part of the mechanism through which GC precipitate brain pathology.
Whole Proteome Clustering of 2,307 Genomes Reveals Remarkable Conservation of Four Proteins Among Proteobacteria While Revealing Significant Annotation Issues
Authors: Lockwood Svetlana , Brayton Kelly A. , Daily Jeff A. , Broschat Shira L. 
Published: June 2018

AbstractTo explore the concept of a minimal gene set, we clustered 8.76 M protein sequences deduced from 2,307 completely sequenced Proteobacterial genomes. To our knowledge this is the first study of this scale. Clustering resulted in 707,311 clusters of which 224,442 ranged in size from 2 to 2,894 sequences. The resulting clusters allowed us to ask the question: Is a set of proteins conserved across all Proteobacteria? We chose four essential proteins, the chaperonin GroEL, DNA dependent RNA polymerase subunits beta and beta’ (RpoB/RpoB’), and DNA polymerase I (PolA), representing fundamental cellular functions, and examined their distribution in the clusters. We found these proteins to be remarkably conserved. Although thegroELgene was universally conserved in all the organisms in the study, the protein was not represented in all the deduced proteomes. The genes for RpoB and RpoB’ were missing from two genomes and merged in 88 genomes, and the sequences were sufficiently divergent that they formed separate clusters for 18 RpoB proteins (seven clusters) and 14 RpoB’ proteins (three clusters). For PolA, 52 organisms lacked an identifiable sequence, and seven sequences were sufficiently divergent that they formed five separate clusters. Interestingly, organisms lacking an identifiable PolA and those with divergent RpoB/RpoB’ were almost all endosymbionts. Furthermore, we present a range of examples of annotation issues that caused the deduced proteins to be incorrectly represented in the proteome. These annotation issues represent a significant obstacle for high throughput analyses.
Mediator is essential for small nuclear and nucleolar RNA transcription in yeast
Authors: Tourigny Jason P. , Saleh Moustafa M. , Zentner Gabriel E. 
Published: June 2018

AbstractEukaryotic RNA polymerase II (RNAPII) transcribes mRNA genes as well as non-protein coding RNAs (ncRNAs) including small nuclear and nucleolar RNAs (sn/snoRNAs). In metazoans, RNAPII transcription of sn/snoRNAs is facilitated by a number of specialized complexes, but no such complexes have been discovered in yeast. It has thus been proposed that yeast sn/snoRNA promoters use the same complement of factors as mRNA promoters, but the extent to which key regulators of mRNA genes act at sn/snoRNA genes in yeast is unclear. Here, we investigated a potential role for the Mediator complex, essential for mRNA gene transcription, in the transcription of sn/snoRNA genes. We found that the complete Mediator complex maps to most sn/snoRNA gene regulatory regions and that loss of Mediator function results in a robust reduction in RNAPII and TFIIB occupancy at sn/snoRNA genes. Furthermore, deletion of subunits of the activator-interacting Mediator tail module does not affect Mediator recruitment to, or transcription of, sn/snoRNAs. Taken together, our analyses indicate that Mediator promotes PIC formation and transcription at sn/snoRNA genes, expanding the role of this critical regulator beyond its known functions in mRNA gene transcription and demonstrating further mechanistic similarity between the transcription of mRNA and sn/snoRNA genes.
Selective sweeps in populations of the broad host range plant pathogenic fungusSclerotinia sclerotiorum
Authors: Derbyshire Mark C , Denton-Giles Matthew , Hane James K , Chang Steven , Mousavi-Derazmahalleh Mahsa , Raffaele Sylvain , Buchwaldt Lone , Kamphuis Lars G 
Published: June 2018

AbstractThe pathogenic fungusSclerotinia sclerotioruminfects over 600 species of plant. It is present in numerous environments throughout the world and causes significant damage to many agricultural crops. Fragmentation and lack of gene flow between populations may lead to population sub-structure. Within discrete recombining populations, positive selection may lead to a ‘selective sweep’. This is characterised by an increase in frequency of a favourable allele leading to reduction in genotypic diversity in a localised genomic region due to the phenomenon of genetic hitchhiking.We aimed to assess whether isolates ofS. sclerotiorumfrom around the world formed genotypic clusters associated with geographical origin and to determine whether signatures of population-specific positive selection could be detected. To do this, we sequenced the genomes of 25 isolates ofS. sclerotiorumcollected from four different continents - Australia, Africa (north and south), Europe and North America (Canada and the northen United States) and conducted SNP based analyses of population structure and selective sweeps.Among the 25 isolates, there was evidence for four population clusters. One of these consisted of 11 isolates from Canada, the USA and France (population 1), another consisted of five isolates from Australia and one from Morocco (population 2). A further cluster was made up of Australian isolates, and the single South African isolate appeared to be from a separate population. We found that there was evidence of distinct selective sweeps between population 1 and population 2. Many of these sweeps overlapped genes involved in transcriptional regulation, such as transcription factors. It is possible that distinct populations ofS. sclerotiorumfrom differing global environments have undergone selective sweeps at different genomic loci. This study lays the foundation for further work into investigation of the differing selective pressures thatS. sclerotiorumpopulations are subjected to on a global scale.
In silicomodeling and simulation of neuroendocrine-immune modulation through adrenergic and 17β-estradiol receptors in lymphocytes show differential activation of cyclic adenosine monophosphate (cAMP)
Authors: Priyanka H. P. , Thiyagaraj A. , Nair R.S. , Krithika G. , Hima L. , Hopper W. , ThyagaRajan S. 
Published: June 2018

AbstractSympathetic innervation of lymphoid organs and presence of 17β-estradiol (estrogen or E2) and adrenergic receptors (ARs) on lymphocytes suggests that sympathetic stimulation and hormonal activation may influence immune functions. Simulation of these pathways may help to understand the dynamics of neuroendocrine-immune modulation at the cellular and molecular level.Dose- and receptor-dependent effects of 17β-estradiol and AR sub-type-specific agonists were established in vitro on lymphocytes from young male Sprague-Dawley rats and modeled in silico using MATLAB Simbiology toolbox. Kinetic principles were assigned to define receptor-ligand dynamics and concentration/time plots were obtained using Ode15s solvers at different time intervals for key regulatory molecules. Comparisons were drawn between in silico andin vitrodata for validating the constructed model with sensitivity analysis of key regulatory molecules to assess their individual impacts on the dynamics of the system.Adrenergic activation triggered pro-apoptotic signals while 17β-estradiol enhanced survival signals showing contradictory effects as observed in vitro. Treatment of lymphocytes with 17β-estradiol shows ten-fold increase in survival signals in a dose-dependent manner. cAMP (cyclic adenosine monophosphate) activation is crucial for the activation of survival signals through p-ERK (Extracellular Signal-Regulated Kinase) and p-CREB (cAMP Responsive Element Binding) protein.Thus, the cross-talk between 17β-estradiol and adrenergic signaling pathways determines lymphocyte functions in a receptor subtype- and co-activation-dependent manner in health and disease.