bluuebunny/crossref_metadata_2025_split huggingface dataset:
Microcrystalline hydroxyapatite is not inferior to fluorides in clinical caries prevention: a randomized, double-blind, non-inferiority trial
Authors: Schlagenhauf Ulrich , Kunzelmann Karl-Heinz , Hannig Christian , May Theodor W. , Hösl Helmut , Gratza Mario , Viergutz Gabriele , Nazet Marco , Schamberger Sebastian , Proff Peter 
Published: April 2018

AbstractRecent evidence for a significant interference of microcrystalline hydroxapatite (HAP) particles with re- and demineralisation processes at the tooth-biofilm interface suggested, that they may be promising candidates for efficacious caries prevention. This multicenter randomized controlled non-inferiority trial evaluated the impact of the 2 x daily use of a HAP dentifrice without fluoride on the progression of enamel caries in adolescent caries-risk patients subjected to orthodontic therapy, with a fluoridated AmF/SnF dentifrice serving as a positive control. Primary study outcome was the occurrence of enamel caries lesions ≥ ICDAS (International Caries Detection and Assessment System) code 1 around orthodontic brackets on the vestibular surfaces of teeth 15-25 within the 168 days observation period. Secondary study outcomes were the occurrence of enamel caries lesion ≥ ICDAS code 2, Plaque Index (PlI) and Gingival Index (GI). Out of 150 recruited patients, 147 were included in the intent to treat analysis (ITT); 133 finished the study per protocol (PP). PP data analysis revealed the occurrence of enamel caries ≥ ICDAS code 1 in 54.7% of the HAP group patients compared to 60.9% of the fluoride control. In the ITT analysis the corresponding numbers were 56.8% (HAP) and 61.6% (control). Non-inferiority testing of the ITT as well as the PP data set proved that the caries preventive efficacy of the HAP dentifrice was not inferior to the protection provided by the fluoridated AmF/SnF control. Regarding all assessed secondary outcomes (enamel caries ≥ ICDAS code 2, GI, PlI) no significant differences between both experimental groups were observed. Within the restraints set by design and study population of this trial microcrystalline HAP as ingredient of toothpaste may thus be regarded a promising supplement to fluorides in clinical caries prevention (ClinicalTrials.gov: NCT02705456).
Population-level HIV incidence estimates using a combination of synthetic cohort and recency biomarker approaches in KwaZulu-Natal, South Africa
Authors: Grebe Eduard , Welte Alex , Johnson Leigh F. , Cutsem Gilles van , Puren Adrian , Ellman Tom , Etard Jean-François ,   the Consortium for the Evaluation and Performance of HIV Incidence Assays (CEPHIA), Huerga Helena 
Published: April 2018

AbstractIntroductionThere is a notable absence of consensus on how to generate estimates ofpopulation-level incidence. Incidence is a considerably more sensitive and harder to estimate indicator of epidemiological trends than prevalence. We used a novel hybrid method to estimate HIV incidence by age and sex in a rural district of KwaZulu-Natal, South Africa.MethodsOur novel method uses an ‘optimal weighting’ of estimates based on an implementation of a particular ‘synthetic cohort’ approach (interpreting the age/time structure of prevalence, in conjunction with estimates of excess mortality) and biomarkers of ‘recent infection’ (combining Lag-Avidity, Bio-Rad Avidity and viral load results to define recent infection, and adapting the method for age-specific incidence estimation). Data were obtained from a population-based cross-sectional HIV survey conducted in Mbongolwane and Eshowe health service areas in 2013.ResultsUsing the combined method, we find that age-specific HIV incidence in females rose rapidly during adolescence, from 1.33 cases/100 person-years (95% CI:0.98,1.67) at age 15 to a peak of 5.01/100PY (4.14,5.87) at age 23. In males, incidence was lower, 0.34/100PY (0.00-0.74) at age 15, and rose later, peaking at 3.86/100PY(2.52-5.20) at age 30. Susceptible population-weighted average incidence in females aged 15-29 was estimated at 3.84/100PY (3.36-4.40), in males aged 15-29 at 1.28/100PY(0.68-1.50) and in all individuals aged 15-29 at 2.55/100PY (2.09-2.76). Using the conventional recency biomarker approach, we estimated HIV incidence among females aged 15-29 at 2.99/100PY (1.79-4.36), among males aged 15-29 at 0.87/100PY(0.22-1.60) and among all individuals aged 15-59 at 1.66/100PY (1.13-2.27).DiscussionHIV incidence was very high in women aged 15-30, peaking in the early 20s. Men had lower incidence, which peaked at age 30. The estimates obtained from the hybrid method are more informative than those produced by conventional analysis of biomarker data, and represents a more optimal use of available data than either the age-continuous biomarker or synthetic cohort methods alone. The method is mainly useful at younger ages, where excess mortality is low and uncertainty in the synthetic cohort estimates is reasonably small.ConclusionApplication of this method to large-scale population-based HIV prevalence surveys is likely to result in improved incidence surveillance over methods currently in wide use. Reasonably accurate and precise age-specific estimates of incidence are important to target better prevention, diagnosis and care strategies.
Relative sensitivity of explicit re-aiming and implicit motor adaptation
Authors: Hutter Sarah A. , Taylor Jordan A. 
Published: April 2018

AbstractIt has become increasingly clear that learning in visuomotor rotation tasks, which induce an angular mismatch between movements of the hand and visual feedback, largely results from the combined effort of two distinct processes: implicit motor adaptation and explicit re-aiming. However, it remains unclear how these two processes work together to produce trial-by-trial learning. Previous work has found that implicit motor adaptation operates automatically, regardless of task relevancy, and saturates for large errors. In contrast, little is known about the automaticity of explicit re-aiming and its sensitivity to error magnitude. Here we sought to characterize the automaticity and sensitivity function of these two processes to determine how they work together to facilitate performance in a visuomotor rotation task. We found that implicit adaptation scales relative to the visual error, but only for small perturbations – replicating prior work. In contrast, explicit re-aiming scales linearly for all tested perturbation sizes. Furthermore, the consistency of the perturbation appears to diminish both implicit adaptation and explicit re-aiming, but to different degrees. Whereas implicit adaptation always displayed a response to the error, explicit re-aiming was only engaged when errors displayed a minimal degree of consistency. This comports with the idea that implicit adaptation is obligatory and less flexible, while explicit re-aiming is volitional and flexible.
Construct validity of five sentiment analysis methods in the text of encounter notes of patients with critical illness
Authors: Weissman Gary E. , Ungar Lyle H. , Harhay Michael O. , Courtright Katherine R. , Halpern Scott D. 
Published: April 2018

AbstractSentiment analysis may offer insights into patient outcomes through the subjective expressions made by clinicians in the text of encounter notes. We analyzed the predictive, concurrent, convergent, and content validity of five sentiment methods in a sample of 791,216 multidisciplinary clinical notes among 40,602 hospitalizations associated with an intensive care unit stay. None of these approaches improved early prediction of in-hospital mortality. However, positive sentiment measured by Pattern (OR 0.09, 95% Cl 0.04 – 0.17), sentimentr (OR 0.37, 95% Cl 0.25 – 0.63), and Opinion (OR 0.25, 95% Cl 0.07 – 0.89) were inversely associated with death on the concurrent day after adjustment for demographic characteristics and illness severity. Median daily lexical coverage ranged from 5.2% to 20.5%. While sentiment between all methods was positively correlated, their agreement was weak. Sentiment analysis holds promise for clinical applications, but will require a novel domain-specific method applicable to clinical text.
CRISPRCloud2: A cloud-based platform for deconvolving CRISPR screen data
Authors: Jeong Hyun-Hwan , Kim Seon Young , Rousseaux Maxime W.C. , Zoghbi Huda Y. , Liu Zhandong 
Published: April 2018

AbstractThe simplicity and cost-effectiveness of CRISPR technology have made high-throughput pooled screening approaches available to many. However, the large amount of sequencing data derived from these studies yields often unwieldy datasets requiring considerable bioinformatic resources to deconvolute data; a feature which is simply not accessible to many wet labs. To address these needs, we have developed a cloud-based webtool CRISPRCloud2 that provides a state-of-the-art accuracy in mapping short reads to CRISPR library, a powerful statistical test that aggregates information across multiple sgRNAs targeting the same gene, a user-friendly data visualization and query interface, as well as easy linking to other CRISPR tools and bioinformatics resources for target prioritization. CRISPRCloud2 is a one-stop shop for labs analyzing CRISPR screen data.
Intron retention as a novel source of cancer neoantigens
Authors: Smart Alicia C. , Margolis Claire A. , Pimentel Harold , He Meng Xiao , Miao Diana , Adeegbe Dennis , Fugmann Tim , Wong Kwok-Kin , Van Allen Eliezer M. 
Published: April 2018

Personalized cancer vaccine strategies directed at tumor neoantigens derived from somatic mutations in the DNA are currently under prospective evaluation1, 2. Alterations in tumor RNA, rather than DNA, may also represent a previously-unexplored source of neoantigens. Here, we show that intron retention, a widespread feature of cancer transcriptomes3, 4, represents a novel source of tumor neoantigens. We developed an in silico approach to identify retained intron neoantigens from RNA sequencing data and applied this methodology to tumor samples from patients with melanoma treated with immune checkpoint blockade5, 6, discovering that the retained intron neoantigen burden in these samples augments the DNA-derived, somatic neoantigen burden. We validated the existence of retained intron derived neoantigens by implementing this technique on cancer cell lines with mass spectrometry-derived immunopeptidome data7, 8, revealing that retained intron neoantigens were complexed with MHC I experimentally. Unexpectedly, we observed a trend toward lack of clinical benefit from immune checkpoint blockade in high retained intron load-tumors, which harbored transcriptional signatures consistent with cell cycle dysregulation and DNA damage repair. Our results demonstrate the contribution of transcriptional dysregulation to the overall burden of tumor neoantigens, provide a foundation for augmenting personalized cancer vaccine development with a new class of tumor neoantigens, and demonstrate how global transcriptional dysregulation may impact selective response to immune checkpoint blockade.Statement of significanceWe developed and experimentally validated a computational pipeline to identify a novel class of tumor neoantigens derived from RNA-based intron retention, which is prevalent throughout cancer transcriptomes. The discovery of transcriptionally-derived tumor neoantigens expands the tumor immunopeptidome and contributes potential substrates for personalized cancer vaccine development.
Mechanism of actin polymerization revealed by cryo-EM structures of actin filaments with three different bound nucleotides
Authors: Chou Steven Z. , Pollard Thomas D. 
Published: April 2018

AbstractWe used electron cryo-micrographs to reconstruct actin filaments with bound AMPPNP (β,γ-imidoadenosine 5’-triphosphate, an ATP analog), ADP-Pi (ADP with inorganic phosphate) or ADP to resolutions of 3.4 Å, 3.4 Å and 3.6 Å. Subunits in the three filaments have nearly identical backbone conformations, so assembly rather than ATP hydrolysis or phosphate dissociation is responsible for their flattened conformation in filaments. Polymerization increases the rate of ATP hydrolysis by changing the conformations of the three ATP phosphates and the side chains of Gln137 and His161 in the active site. Flattening also promotes interactions along both the long-pitch and short-pitch helices. In particular, conformational changes in subdomain 3 open up favorable interactions with the DNase-I binding loop in subdomain 2 of the adjacent subunit. Subunits at the barbed end of the filament are likely to be in this favorable conformation, while monomers are not. This difference explains why filaments grow faster at the barbed end than the pointed end. Loss of hydrogen bonds after phosphate dissociation may account for the greater flexibility of ADP-actin filaments.Significance StatementActin filaments comprise a major part of the cytoskeleton of eukaryotic cells and serve as tracks for myosin motor proteins. The filaments assemble from actin monomers with a bound ATP. After polymerization, actin rapidly hydrolyzes the bound ATP and slowly dissociates the γ-phosphate. ADP-actin filaments then disassemble to recycle the subunits. Understanding how actin filaments assemble, disassemble and interact with numerous regulatory proteins depends on knowing the structure of the filament. High quality structures of ADP-actin filaments were available, but not of filaments with bound ATP- or with ADP and phosphate. We determined structures of actin filaments with bound AMPPNP (a slowly hydrolyzed ATP analog), ADP and phosphate and ADP by cryo-electron microscopy. These structures show how conformational changes during actin assembly promote ATP hydrolysis and faster growth at one end of the filament than the other.
Differentiation of vegetative cells into spores: a kinetic model applied toBacillus subtilis
Authors: Gauvry Emilie , Mathot Anne-Gabrielle , Couvert Olivier , Leguérinel Ivan , Jules Matthieu , Coroller Louis 
Published: April 2018

AbstractBacterial spores are formed within vegetative cells as thick-walled bodies resistant to physical and chemical treatments which allow the persistence and dissemination of the bacterial species. Spore-forming bacteria are natural contaminants of food raw materials and sporulation can occur in many environments from farm to fork. In order to predict spore formation over time, we developed a model that describes both the kinetics of growth and the differentiation of vegetative cells into spores. The model includes a classical growth model with the addition of only two sporulation-specific parameters: the probability of each vegetative cell to sporulate, and the time needed to form a spore once the cell is committed to sporulation. The growth-sporulation model was evaluated using the spore-forming, Gram positive bacterium,Bacillus subtilisand the biological meaning of the sporulation-specific parameters was validated using a derivative strain that produces the green fluorescent protein as a marker of sporulation initiation. The model accurately describes the growth and the sporulation kinetics in different environmental conditions and further provides valuable, physiological information on the temporal abilities of vegetative cells to differentiate into spores.ImportanceThe growth-sporulation model we developed accurately describes growth and sporulation kinetics. It describes the progressive transition from vegetative cells to spores with sporulation parameters which are meaningful and relevant to the sporulation process. The first parameter is the mean time required for a vegetative cell to differentiate into a spore (i.e. the duration of the sporulation process). The second sporulation parameter is the probability of each vegetative cell forming a spore over time. This parameter assesses how efficient the sporulation process is, how fast vegetative cells sporulate and how synchronous the bacterial population is for sporulation. The model constitutes a very interesting tool to describe the growth and the sporulation kinetics in different environmental conditions and it provides qualitative information on the sporulation of a bacterial population over time.
Temporal development of Drosophila embryos is highly robust across a wide temperature range
Authors: Chong Jeronica , Amourda Christopher , Saunders Timothy E. 
Published: April 2018

AbstractDevelopment is a precisely coordinated process in both space and time. Spatial precision has been quantified in a number of developmental systems, and, for example, such data has contributed significantly to our understanding of morphogen gradient interpretation. However, comparatively little quantitative analysis has been performed on timing and temporal coordination during development. Here, we use Drosophila to explore the temporal robustness of embryonic development within physiologically normal temperatures. We find that development is temporally very precise across a wide range of temperatures in all three Drosophila species investigated. However, we find temperature dependence in the heterochronicity. A simple model incorporating history-dependence can explain the developmental temporal trajectories. Interestingly, the history-dependence is temperature specific with either effective negative or positive feedback at different temperatures. We also find that embryos are surprisingly robust to shifting temperatures during embryogenesis. We further identify differences between tropical and temperate species that are suggestive of different potential mechanisms regulating temporal development depending on the local environment. Overall, our data shows that Drosophila embryonic development is temporally robust across a wide range of temperatures but there are species specific differences.
Interaction of BIR2/3 of XIAP with E2F1/Sp1 Activates MMP2 and Bladder Cancer Invasion by Inhibiting Src Translation
Authors: Xu Jiheng , Jin Honglei , Li Jingxia , Zhu Junlan , Hua Xiaohui , Tian Zhongxian , Huang Maowen , Yang Rui , Huang Haishan , Huang Chuanshu 
Published: April 2018

AbstractAlthough X-linked inhibitor of apoptosis protein (XIAP) is associated with cancer cell behaviors, the structure-based function of XIAP in promotion human bladder cancer (BC) invasion is barely explored. Herein, we discovered that ectopic expression of the BIR domains of XIAP rescued the MMP2 activation and invasion in XIAP-deleted BC cells, while Src was further defined as a XIAP downstream negative regulator for MMP2 activation and BC invasion. The inhibition of Src expression by BIR domains was caused by attenuation of Src protein translation upon miR-203 upregulation resulting from direct interaction of BIR2 and BIR3 with E2F1 and Sp1, consequently leading to fully activation of E2F1/Sp1. Our findings provide a novel insight into understanding of specific function of BIR2 and BIR3 of XIAP in BC invasion, which will be highly significant for the design/synthesis of new BIR2/BIR3-based compounds for invasive BC treatment.
Global immune fingerprinting in glioblastoma reveals immune-suppression signatures associated with prognosis
Authors: Alban Tyler J. , Alvarado Alvaro G. , Sorensen Mia D. , Bayik Defne , Volovetz Josephine , Serbinowski Emily , Mulkearns-Hubert Erin E. , Sinyuk Maksim , Hale James S. , Onzi Giovana R. , McGraw Mary , Huang Pengjing , Grabowski Matthew M. , Wathen Connor A. , Radivoyevitch Tomas , Kornblum Harley I. , Kristensen Bjarne W. , Vogelbaum Michael A. , Lathia Justin D. 
Published: April 2018

Abstract/SummaryGlioblastoma (GBM) remains uniformly lethal, and, despite a large accumulation of immune cells in the microenvironment, there is limited anti-tumor immune response, even with newly developed immune checkpoint therapies. To overcome these challenges and enhance the efficacy of immunotherapies, a comprehensive understanding of the immune system in GBM and changes during disease progression is required. Here, we integrated multi-parameter flow cytometry and mass cytometry time of flight (CyTOF) analysis of patient blood to determine changes in the immune system among tumor types and over disease progression. Utilizing multi-parameter flow cytometry analysis in a cohort of over 250 patients with brain tumors ranging from benign to malignant primary and metastatic, we found that GBM patients had a significant elevation in myeloid-derived suppressor cells (MDSCs) in blood, but not immunosuppressive T regulatory cells. We validated these findings in GBM patient tissue and found that increased numbers of MDSCs in recurrent GBM portended poor prognosis. CyTOF analysis of peripheral blood from a cohort of newly diagnosed GBM patients revealed that reduction in MDSC frequency over time is accompanied by a concomitant increase in dendritic cells and natural killer cells. This reduced MDSC profile was present in GBM patients with extended survival and was similar to that of low-grade glioma (LGG) patients. Our findings provide a rationale for developing strategies to target MDSCs, which are elevated in GBM patients and predict poor prognosis, either by directly targeting or by shifting the immune profile to induce differentiation toward the immune profile of LGGs.
Circulating microRNA biomarkers for metastatic disease in neuroblastoma patients
Authors: Zeka Fjoralba , Van Goethem Alan , Vanderheyden Katrien , Demuynck Fleur , Lammens Tim , Decock Anneleen , Helsmoortel Hetty H , Vermeulen Joëlle , Noguera Rosa , Berbegall Ana P , Combaret Valérie , Schleiermacher Gudrun , Laureys Geneviève , Schramm Alexander , Schulte Johannes H , Rahmann Sven , Bienertová-Vašků Julie , Mazánek Pavel , Jeison Marta , Ash Shifra , Hogarty Michael D , Moreno-Smith Mirthala , Barbieri Eveline , Shohet Jason , Berthold Frank , Speleman Frank , Fischer Matthias , De Preter Katleen , Mestdagh Pieter , Vandesompele Jo 
Published: April 2018

AbstractIn this study, the circulating miRNome from diagnostic neuroblastoma serum was assessed for identification of non-invasive biomarkers with potential in monitoring metastatic disease. After determining the circulating neuroblastoma miRNome, 743 miRNAs were screened in two independent cohorts of 131 and 54 patients. Evaluation of serum miRNA variance in a model testing for tumor stage, MYCN status, age at diagnosis and overall survival, revealed tumor stage as the most significant factor impacting miRNA abundance in neuroblastoma serum. Differential expression analysis between patients with metastatic and localized disease revealed 9 miRNAs strongly associated with metastatic stage 4 disease in both patient cohorts. Increasing levels of these miRNAs were also observed in serum from xenografted mice bearing human neuroblastoma tumors. Moreover, murine serum miRNA levels were strongly associated with tumor volume, suggesting this miRNA signature may be applied to monitor disease burden.
Claudin-4 Reconstituted in Unilamellar Vesicles is Sufficient to Form Tight Interfaces that Partition Membrane Proteins
Authors: Belardi Brian , Son Sungmin , Vahey Michael D. , Wang Jinzhi , Hou Jianghui , Fletcher Daniel A. 
Published: April 2018

AbstractTight junctions have been hypothesized to act as molecular fences in the plasma membrane of epithelial cells, helping to form differentiated apical and basolateral domains. While this fence function is believed to arise from the interaction of four-pass transmembrane claudins, the complexity of tight junctions has made direct evidence of their role as a putative diffusion barrier difficult to obtain. Here we address this challenge by reconstituting claudin-4 into giant unilamellar vesicles using microfluidic jetting. We find that reconstituted claudin-4 is sufficient to form adhesive interfaces between unilamellar vesicles without accessory proteins present in vivo. By controlling the molecular composition of the inner and outer leaflets of jetted membranes, we show that claudin-4-mediated interfaces can drive partitioning of extracellular membrane proteins but not of inner or outer leaflet lipids. Our findings indicate that homotypic interactions of claudins and their small size can contribute to the polarization of epithelial cells.