bluuebunny/crossref_metadata_2025_split huggingface dataset:
Root caries on aParanthropus robustusthird molar from Drimolen
Authors: Towle Ian , Riga Alessandro , Irish Joel D. , Dori Irene , Menter Colin , Moggi-Cecchi Jacopo 
Published: March 2019

AbstractObjectivesDental caries is often perceived as a modern human disease. However, their presence is documented in many early human groups, various non-human primates and, increasingly, our hominin ancestors and relatives. In this study we describe an antemortem lesion on the root of aParanthropus robustusthird molar from Drimolen, South Africa, which likely represents another example of caries in fossil hominins.Materials and MethodsThe molar, DNH 40, is dated to 2.0–1.5 Ma and displays a lesion on the mesial root surface, extending from the cementoenamel junction 3 mm down toward the apex. The position and severity of the lesion was macroscopically recorded and micro-CT scanned to determine the extent of dentine involvement.ResultsA differential diagnosis indicates root caries, as the lesion is indistinguishable from clinical examples. Although necrotic in appearance, external tertiary dentine is evident on a micro CT scan. Gingival recession and/or continuous eruption of the tooth as a result of extensive occlusal wear would have occurred to facilitate caries formation. Therefore, the lesion is likely linked to relative old age of this individual.DiscussionThis new example increases the total number of carious lesions described inP. robustusteeth to 12, on occlusal, interproximal and, now, root surfaces. Beyond the consumption of caries-causing food(s), caries formation would have also required the presence of requisite intra-oral cariogenic bacteria in this individual and the species. Of interest, the presence of tertiary dentine on the outward surface suggests the DNH 40 lesion may have been arrested, i.e., no longer active, perhaps relating to a change in diet or oral microbiome just prior to the individual’s death.
Relation of in-utero exposure to antiepileptic drugs to pregnancy duration and size at birth
Authors: Margulis Andrea V , Hernandez-Diaz Sonia , McElrath Thomas , Rothman Kenneth J , Plana Estel , Almqvist Catarina , D’Onofrio Brian M , Oberg Anna Sara 
Published: March 2019

ABSTRACTBackgroundThe associations of individual antiepileptic drugs (AEDs) with pregnancy duration and size at birth, and potential dose relations, are not well characterized.MethodsThis cohort study used nationwide Swedish register data (1996-2013). Adjusting for smoking, epilepsy and other AED indications, we used linear and quantile regression to explore associations with pregnancy duration, and birth weight, length, and head circumference (the last three operationalized as z-scores). We used logistic regression for preterm delivery, small for gestational age, and microcephaly. Lamotrigine was the reference drug.Results6,720 infants were exposed to AEDs in utero; AED exposure increased over the study period. Relative to lamotrigine-exposed infants, carbamazepine-exposed infants were born, on average, 1.3 days earlier (mean [95% confidence interval]: −1.3 [−2.3 to −0.3]); were 0.1 standard deviations (SDs) lighter (−0.1 [−0.2 to 0.0]); and had a head circumference that was 0.2 SDs smaller (−0.2 [−0.3 to −0.1]). Pregabalin-exposed infants were born, on average, 1.1 days earlier (1.1 [−3.0 to 0.8]); were 0.1 SDs lighter (−0.1 [−0.3 to 0.0]); and had the same head circumference. Levetiracetam-exposed infants were born, on average, 0.5 days earlier (−0.5 [−2.6 to 1.6]); were 0. 1 SDs lighter (−0.1 [−0.3 to 0.0]); and were 0.1 SDs smaller (−0.1 [−0.3 to 0.1]) in head circumference. Valproic acid–exposed infants had, on average, the same duration of gestation and birth weight z-score, but were 0.2 SDs smaller (−0.2 [−0.2 to −0.1]) in head circumference. More negative associations at the left tail of pregnancy duration and birth weight z-score, effect-measure modification, and dose-response relations were noted for some of the associations. Observed associations were generally of smaller magnitude than that of smoking, assessed as a potential confounder in the same models.ConclusionsIn comparison with lamotrigine, valproic acid and carbamazepine had a more negative association with head circumference than other study AEDs.
Perceptions, attitudes and practices towards scabies in communities on the Bijagós Islands, Guinea-Bissau
Authors: Lopes Maria João , da Silva Eunice Teixeira , Ca Janete , Gonçalves Adriana , Rodrigues Amabelia , Manjuba Cristóvão , Nakutum Jose , D’Alessandro Umberto , Achan Jane , Logan James , Bailey Robin , Last Anna , Walker Steve , Marks Michael 
Published: March 2019

AbstractIntroductionScabies is highly endemic among impoverished populations and has been recently included in the WHO’s list of neglected tropical diseases (NTDs). Community support and behavioural changes are essential for the success of control interventions. This study aimed to explore beliefs, prevention attitudes and health care-seeking behaviours towards scabies in the Bijagós Archipelago of Guinea-Bissau.MethodsData were collected through two methods. Community key informants (community members, community health workers, healthcare workers and traditional healers) were interviewed using snowball sampling. A questionnaire covering perceptions, attitudes and practices was administered to community members using random cluster sampling. Thematic analysis of qualitative data was applied to identify themes. Descriptive statistics were used for quantitative data analysis.ResultsThere was a satisfactory awareness about scabies, but perceptions about disease causation and transmission were imprecise. Misconceptions about personal hygiene as the primary measure for scabies prevention were recurrent. Some participants recognised the importance of early treatment to interrupt transmission. Treatment of close contacts was not considered important. Costs were the main determining factor for treatment choice between traditional healer and the local health centre. Late presentation and delayed treatment were common and associated with poverty and stigmatisation. Scabies impaired quality of life by affecting social interactions, health, fitness to work and school attendance.ConclusionsThere is a need to improve education, recognition, management and affordable access to treatment. Community education, healthcare workers’ training and skin NTDs integrated control programmes should address the challenges highlighted in this study.Authors SummaryScabies is a common skin infection in low income settings. We conducted a study in Guinea-Bissau to explore the knowledge, attitudes and practices about scabies. We conducted interviews with healthcare workers, traditional healers and community members and additionally used an oral-administered questionnaire with a larger sample of community residents. Most individuals had knowledge of scabies and were aware that person to person transmission occurred. However personal and environmental hygiene were both incorrectly identified as particularly important in the transmission of scabies. Cost played a major role in determining where individuals sought care and both poverty and disease associated stigma resulted in delays seeking care. There is a need to improve community and health care worker education about scabies and improve affordable access to treatment.
Estimating statistical power for event-related potential studies using the late positive potential
Authors: Gibney Kyla D. , Kypriotakis George , Cinciripini Paul M. , Robinson Jason D. , Minnix Jennifer A. , Versace Francesco 
Published: March 2019

ABSTRACTThe late positive potential (LPP) is a common measurement used to study emotional processes of subjects in event-related potential (ERP) paradigms. Despite its extensive use in affective neuroscience, there is presently no gold standard for how to appropriately power ERP studies using the LPP in within-subject and between-subjects experimental designs. The present study investigates how the number of trials, number of subjects, and magnitude of the effect size affect statistical power in analyses of the LPP. Using Monte Carlo simulations of ERP experiments with varying numbers of trials, subjects, and effect sizes, we measured the probability of obtaining a statistically significant effect in 1,489 different experiments repeated 1,000 times each. Predictably, our results showed that statistical power increases with increasing numbers of trials and subjects and at larger effect sizes. In addition, we found that higher levels of statistical power can be achieved with lower numbers of subjects and trials and at lower effect sizes in within-subject than in between-subjects designs. Furthermore, we found that, as subjects are added to an experiment, the slope of the relationship between effect size and statistical power increases and shifts to the left until the power asymptotes to nearly 100% at higher effect sizes. This suggests that adding more subjects greatly increases statistical power at lower effect sizes (<1 µV) compared with more robust (>1.5 µV) effect sizes.
Towards accurate high-throughput ligand affinity prediction by exploiting structural ensembles, docking metrics and ligand similarity
Authors: Schneider Melanie , Pons Jean-Luc , Bourguet William , Labesse Gilles 
Published: March 2019

AbstractMotivationNowadays, virtual screening (VS) plays a major role in the process of drug development. Nonetheless, an accurate estimation of binding affinities, which is crucial at all stages, is not trivial and may require target-specific fine-tuning. Furthermore, drug design also requires improved predictions for putative secondary targets among which is Estrogen Receptor alpha (ERα).ResultsVS based on combinations of Structure-Based VS (SBVS) and Ligand-Based VS (LBVS) is gaining momentum to help characterizing secondary targets of xenobiotics (including drugs and pollutants). In this study, we propose an integrated approach using ligand docking based on multiple structural en-sembles to reflect the conformational flexibility of the receptor. Then, we investigate the impact of the two different types of features (structure-based docking descriptors and ligand-based molecular descriptors) for affinity predictions based on a random forest algorithm. We find that ligand-based features have limited predictive power (rP=0.69,R2=0.47), compared to structure-based features (rP=0.78,R2=0.60) while their combination maintains the overall accuracy (rP=0.77,R2=0.56). Extending the training dataset to include xenobiotics, leads to a novel high-throughput affinity prediction method for ERαligands (rP=0.85,R2=0.71). Method’s robustness is tested on several ligand databases and performances are compared with existing rescoring procedures. The presented prediction tool is provided to the community as a dedicated satellite of the @TOME server.Availabilityhttp://atome4.cbs.cnrs.fr/ATOME_V3/SERVER/EDMon_v3.htmlContactschneider@cbs.cnrs.fr,labesse@cbs.cnrs.fr
Dopamine transients delivered in learning contexts do not act as model-free prediction errors
Authors: Sharpe Melissa J. , Batchelor Hannah M. , Mueller Lauren E. , Chang Chun Yun , Maes Etienne J.P. , Niv Yael , Schoenbaum Geoffrey 
Published: March 2019

AbstractDopamine neurons fire transiently in response to unexpected rewards. These neural correlates are proposed to signal the reward prediction error described in model-free reinforcement learning algorithms. This error term represents the unpredicted or ‘excess’ value of the rewarding event. In model-free reinforcement learning, this value is then stored as part of the learned value of any antecedent cues, contexts or events, making them intrinsically valuable, independent of the specific rewarding event that caused the prediction error. In support of equivalence between dopamine transients and this model-free error term, proponents cite causal optogenetic studies showing that artificially induced dopamine transients cause lasting changes in behavior. Yet none of these studies directly demonstrate the presence of cached value under conditions appropriate for associative learning. To address this gap in our knowledge, we conducted three studies where we optogenetically activated dopamine neurons while rats were learning associative relationships, both with and without reward. In each experiment, the antecedent cues failed to acquired value and instead entered into value-independent associative relationships with the other cues or rewards. These results show that dopamine transients, constrained within appropriate learning situations, support valueless associative learning.
Structural Basis for the Clamping and Ca2+Activation of SNARE-mediated Fusion by Synaptotagmin
Authors: Grushin Kirill , Wang Jing , Coleman Jeff , Rothman James E. , Sindelar Charles E. , Krishnakumar Shyam S. 
Published: March 2019

AbstractSynapotagmin-1 (Syt1) interacts with both SNARE proteins and lipid membranes to synchronize neurotransmitter release to Ca2+-influx. To understand the underlying molecular mechanism, we determined the structure of the Syt1-SNARE complex on lipid membranes using cryo-electron microscopy. Under resting conditions, the Syt1 C2 domains adopt a novel membrane orientation with a Mg2+-mediated partial insertion of the aliphatic loops, alongside weak interactions with the anionic lipid headgroups. The C2B domain concurrently binds the SNARE bundle via the ‘primary’ interface and is positioned between the SNAREpins and the membrane. In this configuration, Syt1 is projected to sterically delay the complete assembly of the associated SNAREpins and thus, contribute to clamping fusion. This Syt1-SNARE organization is disrupted upon Ca2+-influx as Syt1 reorients into the membrane, allowing the attached SNAREpins to complete zippering and drive fusion. Overall, we find cation (Mg2+/Ca2+) dependent membrane interaction is a key determinant of the dual clamp/activator function of Syt1.
The fitness cost and benefit of phase separated protein deposits
Authors: Sanchez de Groot Natalia , Burgas Marc Torrent , Ravarani Charles N. J. , Trusina Ala , Ventura Salvador , Babu M. Madan 
Published: March 2019

ABSTRACTPhase separation of soluble proteins into insoluble deposits is associated with numerous diseases. However, protein deposits can also function as membrane-less compartments for many cellular processes. What are the fitness costs and benefits of forming such deposits in different conditions? Using a model protein that phase separates into deposits, we distinguish and quantify the fitness contribution due to the loss or gain of protein function and deposit formation in yeast. The environmental condition and the cellular demand for the protein function emerge as key determinants of fitness. Protein deposit formation can lead to cell-to-cell differences in free protein abundance between individuals. This results in variable manifestation of protein function and a continuous range of phenotypes in a cell population, favoring survival of some individuals in certain environments. Thus, protein deposit formation by phase separation might be a mechanism to sense protein concentration in cells and to generate phenotypic variability. The selectable phenotypic variability, previously described for prions, could be a general property of proteins that can form phase separated assemblies and may influence cell fitness.Stand-first textUsing a model protein that phase separates into deposits, we distinguish and quantify the fitness contribution due to the loss or gain of protein function and deposit formation in yeast.Bullet pointsThe presented approach identifies and quantifies different fitness effects associated with protein deposit formation due to phase separationThe environmental condition and the cellular demand for the protein function emerge as key determinants of fitness upon protein deposit formationVariability in protein deposit formation can lead to cell-to-cell differences in free protein abundance between individualsProtein phase separation can generate a continuous range of phenotypes in a cell population
G1/S transcription factors assemble in discrete clusters that increase in number as cells grow
Authors: Black Labe , Tollis Sylvain , Fu Guo , Fiche Jean-Bernard , Dorsey Savanna , Cheng Jing , Ghazal Ghada , Notley Stephen , Crevier Benjamin , Bigness Jeremy , Nollmann Marcelo , Tyers Mike , Royer Catherine A. 
Published: March 2019

AbstractThe spatio-temporal organization of transcription factor (TF)-promoter interactions is critical for the coordination of transcriptional programs. In budding yeast, the main G1/S transcription factors, SBF and MBF, are limiting with respect to target promoters in small G1 phase cells and accumulate as cells grow, raising the question of how SBF/MBF are dynamically distributed across the G1/S regulon. Super-resolution Photo-Activatable Localization Microscopy (PALM) mapping of the static positions of SBF/MBF subunits revealed that 85% were organized into discrete clusters containing ∼8 copies regardless of cell size, while the number of clusters increased with growth. Stochastic simulations with a mathematical model based on co-localization of promoters in clusters recapitulated observed cluster behavior. A prediction of the model that SBF/MBF should exhibit both fast and slow dynamics was confirmed in PALM experiments on live cells. This spatio-temporal organization of the TFs that activate the G1/S regulon may help coordinate commitment to division.
Metformin rescues muscle function in BAG3 myofibrillar myopathy models
Authors: Ruparelia Avnika A. , McKaige Emily A. , Williams Caitlin , Schulze Keith E. , Fuchs Margit , Oorschot Viola , Lacene Emmanuelle , Mirella Meregalli , Baxter Emily C. , Torrente Yvan , Ramm Georg , Stojkovic Tanya , Lavoie Josée N. , Bryson-Richardson Robert J. 
Published: March 2019

AbstractDominant de novo mutations in the co-chaperone BAG3 cause a severe form of myofibrillar myopathy, exhibiting progressive muscle weakness, muscle structural failure, and protein aggregation.To identify therapies we generated two zebrafish models, one conditionally expressing BAG3P209L and one with a nonsense mutation in bag3. Whilst transgenic BAG3P209L expressing fish display protein aggregation, modelling the early phase of the disease, bag3−/− fish demonstrate impaired autophagic activity, exercise dependent fibre disintegration, and reduced swimming activity, consistent with later stages.We confirmed the presence of impaired autophagy in patient samples and screened autophagy promoting compounds for their effectiveness at removing protein aggregates, identifying nine including Metformin. Further evaluation demonstrated Metformin is not only able to remove the protein aggregates in zebrafish and human myoblasts but is also able to rescue the fibre disintegration and swimming deficit observed in the bag3−/− fish. Therefore, repurposing Metformin provides a promising therapy for BAG3 myopathy.
Overexpression of the Rieske FeS protein of the Cytochromeb6fcomplex increases C4photosynthesis
Authors: Ermakova Maria , Lopez-Calcagno Patricia E. , Raines Christine A. , Furbank Robert T. , von Caemmerer Susanne 
Published: March 2019

AbstractC4plants contribute 20% to the global primary productivity despite representing only 4% of higher plant species. Their CO2concentrating mechanism operating between mesophyll and bundle sheath cells increases CO2partial pressure at the site of Rubisco and hence photosynthetic efficiency. Electron transport chains in both cell types supply ATP and NADPH for C4photosynthesis. Since Cytochromeb6fis a key point of control of electron transport in C3plants, we constitutively overexpressed the Rieske FeS subunit inSetaria viridisto study the effects on C4photosynthesis. Rieske FeS overexpression resulted in a higher content of Cytochromeb6fin both mesophyll and bundle sheath cells without marked changes in abundances of other photosynthetic complexes and Rubisco. Plants with higher Cytochromeb6fabundance showed better light conversion efficiency in both Photosystems and could generate higher proton-motive force across the thylakoid membrane. Rieske FeS abundance correlated with CO2assimilation rate and plants with a 10% increase in Rieske FeS content showed a 10% increase in CO2assimilation rate at ambient and saturating CO2and high light. Our results demonstrate that Cytochromeb6fcontrols the rate of electron transport in C4plants and that removing electron transport limitations can increase the rate of C4photosynthesis.
Forward modelling reveals dynamics of neural orientation tuning to unconscious visual stimuli during binocular rivalry
Authors: Tang Matthew F. , Arabzadeh Ehsan , Mattingley Jason B. 
Published: March 2019

AbstractWhen different visual stimuli are presented to the two eyes, they typically compete for access to conscious perception, a phenomenon known as binocular rivalry. Previous studies of binocular rivalry have shown that neural responses to consciously suppressed stimuli are markedly diminished in magnitude, though they may still be encoded to some extent. Here we employed multivariate forward modelling of human electroencephalography (EEG) data to quantify orientation-selective responses to visual gratings during binocular rivalry. We found robust orientation tuning to both conscious and unconscious gratings. This tuning was enhanced for the suppressed stimulus well before it was available for conscious report. The same pattern was evident in the overall magnitude of neural responses, and it emerged even earlier than the changes in neural tuning. Taken together, our findings suggest that rivalry suppression affects broadband, non-orientation selective aspects of neural activity before refining fine-grained feature-selective information.
Entrainment of local synchrony reveals a causal role for high-beta right frontal oscillations in human visual consciousness
Authors: Vernet Marine , Stengel Chloé , Quentin Romain , Amengual Julià L. , Valero-Cabré Antoni 
Published: March 2019

AbstractPrior evidence supports the critical role of oscillatory activity in cognitive function, but are cerebral oscillations simply correlated or causally linked to specific aspects of visual cognition? Here, EEG signals were recorded on humans performing a conscious visual detection task, while they received briefrhythmicorrandomnoninvasive stimulation patterns delivered to the right Frontal Eye Field prior to the onset of a lateralized target. Compared torandompatterns,rhythmichigh-beta patterns led to greater entrainment of local oscillations (i.e., increased power and phase alignment at the stimulation frequency), and to higher conscious detection of contralateral targets. When stimulation succeeded in enhancing visual detection, the magnitude of oscillation entrainment correlated with visual performance increases. Our study demonstrates a causal link between high-beta oscillatory activity in the Frontal Eye Field and conscious visual perception. Furthermore, it supports future applications of brain stimulation to manipulate local synchrony and improve or restore impaired visual behaviors.