bluuebunny/crossref_metadata_2025_split huggingface dataset:
U-shape short-range extrinsic connectivity organisation around the human central sulcus
Authors: Pron Alexandre , Deruelle Christine , Coulon Olivier 
Published: May 2020

AbstractThe central sulcus is probably one of the most studied folds in the human brain, owing to its clear relationship with primary sensory-motor functional areas. However, due to the difficulty of estimating the trajectories of the U-shape fibres from diffusion MRI, the short structural connectivity of this sulcus remains relatively unknown. In this context, we studied the spatial organization of these U-shape fibres along the central sulcus. Based on high quality diffusion MRI data of 100 right-handed subjects and state-of-the-art pre-processing pipeline, we first define a connectivity space that provide a comprehensive and continuous description of the short-range anatomical connectivity around the central sulcus at both the individual and group levels. We then infer the presence of five major U-shape fibre bundles at the group level in both hemispheres by applying unsupervised clustering in the connectivity space. We propose a quantitative investigation of their position and number of streamlines as a function of phenotypic traits such as sex and hemispheres and functional scores such as handedness and manual dexterity. Main findings of this study are twofold: a description of U-shape short-range connectivity along the central sulcus at group level and the evidence of a significant relationship between the position of three hand related U-shape fibre bundles and the handedness score of subjects.
A kinetic ensemble of the Alzheimer’s Aβ peptide
Authors: Löhr Thomas , Kohlhoff Kai , Heller Gabriella T. , Camilloni Carlo , Vendruscolo Michele 
Published: May 2020

AbstractThe discovery that disordered proteins are widespread in the human proteome has prompted the quest for methods to characterize the conformational properties that determine their functional and dysfunctional behaviour. It has become customary to describe these proteins in terms of structural ensembles and free energy landscapes, which offer conformational and thermodynamic insight. However, a current major challenge is to generalize this description to ‘kinetic ensembles’, thereby also providing information on transition rates between states. Approaches based on the theory of stochastic processes can be particularly suitable for this purpose. Here, we develop a Markov state model and illustrate its application by determining a kinetic ensemble of the 42-residue form of the amyloid-β peptide (Aβ42), whose aggregation is associated with Alzheimer’s disease. Using the Google Compute Engine, we generated 315 μs all-atom, explicit solvent molecular dynamics trajectories, validated with experimental data from nuclear magnetic resonance spectroscopy. Using a probabilistic-based definition of conformational states in a neural network approach, we found that Aβ42 is characterized by inter-state transitions no longer than the microsecond timescale, exhibiting only fully unfolded or short-lived, partially-folded states. We contextualize our findings by performing additional simulations of the oxidized form of Aβ42. Our results illustrate how the use of kinetic ensembles offers an effective means to provide information about the structure, thermodynamics, and kinetics of disordered proteins towards an understanding of these ubiquitous biomolecules.
A two-trick pony: lysosomal protease cathepsin B possesses surprising ligase activity
Authors: Lambeth Tyler R. , Dai Zhefu , Zhang Yong , Julian Ryan R. 
Published: May 2020

AbstractCathepsin B is an important protease within the lysosome, where it helps recycle proteins to maintain proteostasis. It is also known to degrade proteins elsewhere but has no other known functionality. However, by carefully monitoring peptide digestion with liquid chromatography and mass spectrometry, we observed synthesis of novel peptides during cathepsin B incubations. This ligation activity was explored further with a variety of peptide substrates to establish mechanistic details and was found to operate through a two-step mechanism with proteolysis and ligation occurring separately. Further explorations using varied sequences indicated increased affinity for some substrates, though all were found to ligate to some extent. Finally, experiments with a proteolytically inactive form of the enzyme yielded no ligation, indicating that the ligation reaction occurs in the same active site but in the reverse direction of proteolysis. These results clearly establish that cathepsin B can act as both a protease and ligase, although protease action eventually dominates over longer periods of time.
Immunization withMycobacterium vaccaeNCTC 11659 prevents the development of PTSD-like sleep and behavioral phenotypes after sleep disruption and acute stress in mice
Authors: Bowers Samuel J. , Lambert Sophie , He Shannon , Lowry Christopher A. , Fleshner Monika , Wright Kenneth P. , Turek Fred W. , Vitaterna Martha H. 
Published: May 2020

AbstractBecause regular sleep disruption can increase vulnerability to stress-related psychiatric disorders, there is a need to explore novel countermeasures to increase stress resilience after inadequate sleep. In this study, we explored the impact of 5 days of intermittent sleep disruption on vulnerability to acute social defeat stress in mice, and investigated the ability of the environmental, immunomodulatory bacteriumMycobacterium vaccaeNCTC 11659 (MV) to promote stress resilience in that context. We found that mice receiving sleep disruption plus acute stress developed sleep and behavioral phenotypes that had some features of human posttraumatic stress disorder (PTSD) including reduced NREM delta power and increased NREM beta power in post-stress sleep EEG, persistent increases in sleep fragmentation and the REM:Sleep ratio, and behavioral changes. Importantly, immunization with heat-killed MV prevented the development of this phenotype. These results support further research into novel, microbial-based countermeasures to improve health and increase resilience to sleep disruption.
Reversing age: dual species measurement of epigenetic age with a single clock
Authors: Horvath Steve , Singh Kavita , Raj Ken , Khairnar Shraddha , Sanghavi Akshay , Shrivastava Agnivesh , Zoller Joseph A. , Li Caesar Z. , Herenu Claudia B. , Canatelli-Mallat Martina , Lehmann Marianne , Solberg Woods Leah C. , Martinez Angel Garcia , Wang Tengfei , Chiavellini Priscila , Levine Andrew J. , Chen Hao , Goya Rodolfo G. , Katcher Harold L. 
Published: May 2020

AbstractYoung blood plasma is known to confer beneficial effects on various organs in mice. However, it was not known whether young plasma rejuvenates cells and tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly-accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=593 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=850 human tissue samples to the training data. We employed these six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging.
Modeling consensus and distance to delivering indoor residual spray (IRS) implementation strategies to control malaria transmission
Authors: Ryan Sadie , Martin Anne C. , Walia Bhavneet , Winters Anna , Larsen David A 
Published: May 2020

AbstractBackgroundIndoor residual spraying (IRS) is an effective method to control malaria-transmittingAnophelesmosquitoes and often complements insecticide-treated mosquito nets, the predominant malaria vector control intervention. With insufficient funds to cover every household, malaria control programs must balance the malaria risk to a particular human community against the financial cost of spraying that community. This study creates a framework for modeling the distance to households for targeting IRS implementation, and applies it to potential risk prioritization strategies in four provinces (Luapula, Muchinga, Eastern, and Northern) in Zambia.MethodsWe used optimal network models to assess the travel distance of routes between operations bases and human communities identified through remote sensing. We compared network travel distances to Euclidean distances, to demonstrate the importance of accounting for road route costs. We then compared the distance to reaching communities for different risk prioritization strategies assuming sufficient funds to spray 50% of households, using four underlying malarial risk maps: a) predictedPlasmodium falciparumparasite rate in 2-10 year olds (PfPR), or b) predicted probability of the presence of each of three main malaria transmitting anopheline vectors (An. arabiensis, An. funestus, An. gambiae)ResultsThe estimated one-way network route distance to reach communities to deliver IRS ranged from 0.05 – 115.69 Km. Euclidean distance over and under-estimated these routes by −101.21 – 41.79 Kmper trip, as compared to the network route method. There was little overlap between risk map prioritization strategies, both at a district-by-district scale, and across all four provinces. At both scales, agreement for inclusion or exclusion from IRS across all four prioritization strategies occurred in less than 10% of houses. The distances to reaching prioritized communities were either lower, or not statistically different from non-prioritized communities, at both scales of strategy.ConclusionVariation in distance to targeted communities differed depending on risk prioritization strategy used, and higher risk prioritization did not necessarily translate into greater distances in reaching a human community. These findings from Zambia suggest that areas with higher malaria burden may not necessarily be more remote than areas with lower malaria burden.
Typical and atypical language brain organization based on intrinsic connectivity and multitask functional asymmetries
Authors: Labache Loïc , Mazoyer Bernard , Joliot Marc , Crivello Fabrice , Hesling Isabelle , Tzourio-Mazoyer Nathalie 
Published: May 2020

ABSTRACTBased on the joint investigation in 287 healthy volunteers (150 Left-Handers (LH)) of language task-induced asymmetries and intrinsic connectivity strength of the sentence-processing supramodal network, we show that individuals with atypical rightward language lateralization (N = 30, 25 LH) do not rely on an organization that simply mirrors that of typical leftward lateralized individuals. Actually, the resting-state organization in the atypicals showed that their sentence processing was underpinned by left and right networks both wired for language processing and highly interacting by strong interhemispheric intrinsic connectivity and larger corpus callosum volume. Such a loose hemispheric specialization for language permits the hosting of language in either the left and/or right hemisphere as assessed by a very high incidence of dissociations across various language task-induced asymmetries in this group.
An unexpected lack of difference in superoxide/H2O2production rates in isolated heart and skeletal muscle mitochondria from a mouse model of Barth Syndrome
Authors: Goncalves Renata L. S. , Schlame Michael , Bartelt Alexander , Brand Martin D. , Hotamışlıgil Gökhan S. 
Published: May 2020

AbstractBarth Syndrome (BTHS) is a rare X-linked genetic disorder caused by mutations in tafazzin and characterized by loss of cardiolipin and severe cardiomyopathy. Mitochondrial superoxide/H2O2production has been implicated in the cardiomyopathy observed in different BTHS models. There are at least 11 mitochondrial sites that produce superoxide/H2O2at significant rates. Which of these sites generate oxidants at excessive rates in BTHS is unknown. Here, we measured the maximum capacity of superoxide/H2O2production from each site in mitochondria isolated from heart and skeletal muscle of the tafazzin knockdown mice (tazkd) at 3, 7 and 12 months of age. Strikingly, the superoxide/H2O2production capacities of these sites were overall indistinguishable between tazkd mice and their wildtype littermates across the time points analyzed. The only exception was site GQin glycerol phosphate dehydrogenase, which was increased in the skeletal muscle of 7 months old tazkd mice. Mitochondrial superoxide/H2O2production was also measuredex vivoduring the oxidation of a complex mixture of substrates mimicking either heart or skeletal muscle cytosol and was found to be indistinguishable between wildtype and tazkd mice. However, we consistently measured decreased FAD-linked respiration in mitochondria isolated from tazkd mice. We conclude that the maximum capacity andex vivorates of superoxide/H2O2production were not increased in mitochondria isolated from heart and skeletal muscle of tazkd mice, despite reduced oxidative capacity. Therefore, it seems unlikely that mitochondrial oxidants contribute to the development of cardiomyopathy in tazkd mice. These observations raise questions about the involvement of mitochondrial oxidants in BTHS pathology.
Oscillatory entrainment mechanisms and anticipatory predictive processes in Autism Spectrum Disorder (ASD)
Authors: Beker Shlomit , Foxe John J. , Molholm Sophie 
Published: May 2020

ABSTRACTAnticipating near-future events is fundamental to adaptive behavior, whereby neural processing of predictable stimuli is significantly facilitated relative to non-predictable inputs. Neural oscillations appear to be a key anticipatory mechanism by which processing of upcoming stimuli is modified, and they often entrain to rhythmic environmental sequences. Clinical and anecdotal observations have led to the hypothesis that people with Autism Spectrum Disorder (ASD) may have deficits in generating predictions in daily life, and as such, a candidate neural mechanism may be failure to adequately entrain neural activity to repetitive environmental patterns. Here, we tested this hypothesis by interrogating rhythmic entrainment both behaviorally and electrophysiologically. We recorded high-density electroencephalography in children with ASD (n=31) and Typically Developing (TD) age- and IQ-matched controls (n=20), while they reacted to an auditory target as quickly as possible. This auditory event was either preceded by predictive rhythmic visual cues, or not. Results showed that while both groups presented highly comparable evoked responses to the visual stimuli, children with ASD showed reduced neural entrainment to the rhythmic visual cues, and altered anticipation of the occurrence of these stimuli. Further, in both groups, neuro-oscillatory phase coherence correlated with behavior. These results describe neural processes that may underlie impaired event anticipation in children with ASD, and support the notion that their perception of events is driven more by instantaneous sensory inputs and less by their temporal predictability.
A comparison of two methods for estimating measurement repeatability in morphometric studies
Authors: Wylde Zachariah , Bonduriansky Russell 
Published: May 2020

SummaryMeasurement repeatability is often reported in morphometric studies as an index of the contribution of measurement error to trait measurements. However, the common method of remeasuring a mounted specimen fails to capture some components of measurement error, and could therefore yield inflated repeatability estimates. Remounting specimens between successive measurements is likely to provide more realistic estimates of repeatability, particularly for small structures that are difficult to measure.Using measurements of 22 somatic and genitalic traits of the neriid flyTelostylinus angusticollis, we compared repeatability estimates obtained via remeasuring (where a mounted specimen is measured twice) versus remounting (where a specimen is remounted between measurements). We also asked whether the difference in repeatability estimates obtained via the two methods depends on trait size.Repeatability estimates obtained via remounting were lower than estimates obtained via remeasuring for each of the 22 traits, and the difference between estimates obtained via the two methods was generally greater for small structures (genitalic traits) than for large structures (legs, wings).Remounting specimens between successive measurements can provide more accurate estimates of measurement repeatability than remeasuring from a single mount, especially for small structures that are difficult to measure.
Automated design of CRISPR prime editors for thousands of human pathogenic variants
Authors: Morris John A. , Rahman Jahan A. , Guo Xinyi , Sanjana Neville E. 
Published: May 2020

AbstractPrime editors (PEs) are CRISPR-based genome engineering tools that can introduce precise base-pair edits at specific locations in the genome. These programmable gene editors have been predicted to repair 89% of known human pathogenic variants in the ClinVar database, although these PE constructs do not presently exist. Towards this end, we developed an automated pipeline to correct (therapeutic editing) or introduce (disease modeling) human pathogenic variants that optimizes the design of several RNA constructs required for prime editing and avoids predicted off-targets in the human genome. However, using optimal PE design criteria, we find that only a small fraction of these pathogenic variants can be targeted. Through the use of alternative Cas9 enzymes and extended templates, we increase the number of targetable pathogenic variants to >50,000 variants and make these pre-designed PE constructs accessible through a web-based portal (http://primeedit.nygenome.org). Given the tremendous potential for therapeutic gene editing, we also assessed the possibility of developing universal PE constructs. By examining the overlap of different PE components with common human genetic variants in dbSNP, we find that common variants affect only a small minority of designed PEs.
Flagellar targeting of an arginine kinase requires a conserved lipidated intraflagellar transport (LIFT) pathway inTrypanosoma brucei
Authors: Pandey Maneesha , Huang Yameng , Lim Teck Kwang , Lin Qingsong , He Cynthia Y. 
Published: May 2020

AbstractBoth intraflagellar transport (IFT) and lipidated intraflagellar transport (LIFT) pathways are essential for cilia/flagella biogenesis, motility and sensory functions. In the LIFT pathway, lipidated cargoes are transported into the cilia through the coordinated actions of cargo carrier proteins such as Unc119 or PDE6δ, as well as small GTPases Arl13b and Arl3 in the cilium. Our previous studies revealed a single Arl13b ortholog in the evolutionarily divergentTrypanosoma brucei. TbArl13 catalyses two TbArl3 homologs, TbArl3A and TbArl3C, suggesting the presence of a conserved LIFT pathway in these protozoan parasites. Only a single homolog to the cargo carrier protein Unc119 was identified inT. bruceigenome, but its function in lipidated protein transport has not been characterized. In this study, we exploited the proximity-based biotinylation approach to identify binding partners of TbUnc119. We showed that TbUnc119 binds to a flagellar arginine kinase TbAK3 in a myristoylation-dependent manner and is responsible for its targeting and enrichment in the flagellum. Interestingly, only TbArl3A, but not TbArl3C interacts with TbUnc119 in a GTP-dependant manner, suggesting functional specialization of Arl3-GTPases inT. brucei. This study establishes the function of TbUnc119 as a myristoylated cargo carrier and supports the presence of a conserved LIFT pathway inT. brucei.
Assessing the variation within the oral microbiome of healthy adults
Authors: Nearing Jacob T. , DeClercq Vanessa , Van Limbergen Johan , Langille Morgan G.I. 
Published: May 2020

AbstractOver 1000 different species of microbes have been found to live within the human oral cavity where they play important roles in maintaining both oral and systemic health. Several studies have identified the core members of this microbial community, however, the factors that determine oral microbiome composition are not well understood. In this study we exam the salivary oral microbiome of 1049 Atlantic Canadians using 16S rRNA gene sequencing in order to determine which dietary, lifestyle, and anthropometric features play a role in shaping microbial community composition. Features that were identified as being significantly associated with overall composition were then additionally examined for genera and amplicon sequence variants that were associated with these features. Several associations were replicated in an additional secondary validation dataset. Overall, we found that several anthropometric measurements including waist hip ratio, height, and fat free mass, as well as age and sex, were associated with oral microbiome composition in both our exploratory and validation cohorts. We were unable to validate dietary impacts on the oral microbiome but did find evidence to suggest potential contributions from factors such as the number of vegetable and refined grain servings an individual consumes. Interestingly, each one of these factors on their own were associated with only minor shifts in the oral microbiome suggesting that future biomarker identification for several diseases associated with the oral microbiome may be undertaken without the worry of confounding factors obscuring biological signal.ImportanceThe human oral cavity is inhabited by a diverse community of microbes known as the human oral microbiome. These microbes play a role in maintaining both oral and systemic health and as such have been proposed to be useful biomarkers of disease. However, to identify these biomarkers, we first need to determine the composition and variation of the healthy oral microbiome. Within this report we investigate the oral microbiome of 1049 healthy individuals to determine which genera and amplicon sequence variants are commonly found between individual oral microbiomes. We then further investigate how lifestyle, anthropometric, and dietary choices impact overall microbiome composition. Interestingly, the results from this investigation showed that while many features were significantly associated with oral microbiome composition no single biological factor explained a variation larger than 2%. These results indicate that future work on biomarker detection may be encourage by the lack of strong confounding factors.