bluuebunny/crossref_metadata_2025_split huggingface dataset:
Applying knowledge-driven mechanistic inference to toxicogenomics
Authors: Tripodi Ignacio J. , Callahan Tiffany J. , Westfall Jessica T. , Meitzer Nayland S. , Dowell Robin D. , Hunter Lawrence E. 
Published: September 2019

AbstractGovernment regulators and others concerned about toxic chemicals in the environment hold that a mechanistic, causal explanation of toxicity is strongly preferred over a statistical or machine learning-based prediction by itself. Elucidating a mechanism of toxicity is, however, a costly and time-consuming process that requires the participation of specialists from a variety of fields, often relying on animal models. We present an innovative mechanistic inference framework (MechSpy), which can be used as a hypothesis generation aid to narrow the scope of mechanistic toxicology analysis. MechSpy generates hypotheses of the most likely mechanisms of toxicity, by combining a semantically-interconnected knowledge representation of human biology, toxicology and biochemistry with gene expression time series on human tissue. Using vector representations of biological entities, MechSpy seeks enrichment in a manually-curated list of high-level mechanisms of toxicity, represented as biochemically- and causally-linked ontology concepts. Besides predicting the canonical mechanism of toxicity for many well-studied compounds, we experimentally validated some of our predictions for other chemicals without an established mechanism of toxicity. This framework can be modified to include additional mechanisms of toxicity, and is generalizable to other types of mechanisms of human biology.Author summarySeveral recent computational methods have displayed excellent performance in predicting toxicity outcomes [1–3] of chemicals. Yet, to our knowledge, there is to date no computational approach to generate mechanistic hypotheses to answer why these chemicals elicit a toxic response. There is great value in understanding the mechanism of toxicity for a chemical that appears to elicit an adverse response. Novel small molecule development is one example, where a chemical that failed initial toxicological screenings could be assessed to evaluate the actual mechanism of toxicity, greatly reducing research time and expenses on subsequent ones. The value of a mechanistic awareness of toxicity also applies to pharmacovigilance, when researching rare adverse effects of a drug in subsets of the population. The development of oncological chemotherapeutics is another example, where certain mechanisms of cytotoxicity can actually be desirable to eliminate different types of tumor cells. More importantly, the costs, time expenditure, and ethical concerns of toxicity animal models, make in vitro and in silico approaches an enticing alternative. We present a solution that uses a combination of gene expression assays and biomedical knowledge to address the gap of answering the why question.
Differential urine proteome analysis of a bovine IRBP induced uveitis rat model by discovery and parallel reaction monitoring proteomics
Authors: Qin Weiwei , Li Lujun , Wang Ting , Gao Youhe 
Published: September 2019

AbstractUveitis, a group of intraocular inflammatory diseases, is one of the major causes of severe visual impairment among working age population. Urine is a promising resource for biomarker research, which could sensitively reflect the changes of the body. This study was designed to explore urinary protein biomarkers for diagnosis and/or monitoring of uveitis. Experimental autoimmune uveitis (EAU) rat model induced by bovine interphotoreceptor retinoid-binding protein (IRBP) was used to mimic the uveitis. In the discovery phase, urine samples from EAU and control rats were analyzed by data independent acquisition (DIA) approach combined with high-resolution mass spectrometry. Overall, 704 high confidential proteins were identified, of which 100 were differentially expressed (37, 33, 37, and 44 on day 5, 8, 12, and 16, respectively, after bovine IRBP immunization) (1.5-fold change, P<0.05). Gene Ontology analysis of the dysregulated proteins showed that chronic inflammatory response, neutrophil aggregation and immune system processes were significantly enriched. Finally, parallel reaction monitoring (PRM) approach was used for further validation. A total of 12 urinary proteins (MMP8, NGAL, HPT, UROM, RISC, A1AG, TTHY, KNT1, C9, PTER, CBG, and FUCA1) changed significantly, even when there is no clinical manifestations and histopathological ocular damages in the EAU rats. Our findings represent the first step towards urinary protein diagnostic biomarkers for uveitis.Biological SignificanceThis is the first study investigating urinary protein candidate biomarkers for uveitis using data independent acquisition (DIA) combined with parallel reaction monitoring (PRM) in experimental autoimmune uveitis (EAU) rats. The results revealed that urine is a promising resource for early diagnostics of uveitis. Further research including clinical urine samples is needed to determine the sensitivity and specificity of these candidate biomarkers for uveitis.
Physiological Differences Between Advanced Crossfit Athletes, Recreational Crossfit Participants, and Physically-Active Adults
Authors: Mangine Gerald T. , Stratton Matthew T. , Almeda Christian G. , Roberts Michael D. , Esmat Tiffany A. , VanDusseldorp Trisha A. , Feito Yuri 
Published: September 2019

ABSTRACTThis investigation examined anthropometric, hormonal, and physiological differences between advanced (ADV; n = 8, 27.8 ± 4.2 years, 170 ± 11 cm, 79.8 ± 13.3 kg) and recreational (REC; n = 8, 33.5 ± 8.1 years, 172 ± 14 cm, 76.3 ± 19.5 kg) CrossFit (CF) trained participants in comparison to physically-active controls (CON; n = 7, 27.5 ± 6.7 years, 171 ± 14 cm, 74.5 ± 14.3 kg). ADV and REC were distinguished by their past competitive success. REC and CON were resistance-trained (>2 years) and exercised on 3-5 days·wk-1for the past year, but CON utilized traditional resistance and cardiovascular exercise. All participants provided a fasted, resting blood sample and completed assessments of resting metabolic rate, body composition, muscle morphology, isometric mid-thigh pull strength, peak aerobic capacity, and a 3-minute maximal cycle ergometer sprint across two separate occasions (separated by 3-7 days). Blood samples were analyzed for testosterone, cortisol, and insulin-like growth factor-1. One-way analysis of variance revealed ADV to possess lower body fat percentage (6.7-8.3%,p= 0.007), greater bone and non-bone lean mass (12.5-26.8%,p≤ 0.028), muscle morphology characteristics (14.2-59.9%,p< 0.05), isometric strength characteristics (15.4-41.8%,p< 0.05), peak aerobic capacity (18.8-19.1%,p= 0.002), and anaerobic performance (15.4-51.1%,p≤ 0.023) compared to both REC and CON. No differences were seen between REC and CON, or between all groups for resting metabolic rate or hormone concentrations. These data suggest ADV possess several physiological advantages over REC and CON, whereas similar physiological characteristics were present in individuals who have been regularly participating in either CF or resistance and cardiovascular training for the past year.
Rab11A regulates the constitutive secretory pathway duringToxoplasma gondiiinvasion of host cells and parasite replication
Authors: Kannan Venugopal , Sylia Chehade , Elisabeth Werkmeister , Nicolas Barois , Javier Periz , Frank Lafont , Isabelle Tardieux , Jamal Khalife , Langsley Gordon , Markus Meissner , Sabrina Marion 
Published: September 2019

SummaryToxoplasma gondiipossesses an armada of secreted virulent factors that enable parasite invasion and survival into host cells. These factors are contained in specific secretory organelles, the rhoptries, micronemes and dense granules that release their content upon host cell recognition. Dense granules are secreted in a constitutive manner during parasite replication and play a crucial role in modulating host metabolic and immune responses. While the molecular mechanisms triggering rhoptry and microneme release upon host cell adhesion have been well studied, constitutive secretion remains a poorly explored aspect ofT. gondiivesicular trafficking. Here, we investigated the role of the small GTPase Rab11A, a known regulator of exocytosis in eukaryotic cells. Our data revealed an essential role of Rab11A in promoting the cytoskeleton driven transport of DG and the release of their content into the vacuolar space. Rab11A also regulates transmembrane protein trafficking and localization during parasite replication, indicating a broader role of Rab11A in cargo exocytosis at the plasma membrane. Moreover, we found that Rab11A also regulates extracellular parasite motility and adhesion to host cells. In line with these findings, MIC2 secretion was altered in Rab11A-defective parasites, which also exhibited severe morphological defects. Strikingly, by live imaging we observed a polarized accumulation of Rab11A-positive vesicles and dense granules at the apical pole of extracellular motile parasites suggesting that a Rab11A-dependent apically polarized transport of cargo regulates parasite motility.
A nucleus-forming jumbophage evades CRISPR-Cas DNA targeting but is vulnerable to type III RNA-based immunity
Authors: Malone Lucia M. , Warring Suzanne L. , Jackson Simon A. , Warnecke Carolin , Gardner Paul P. , Gumy Laura F. , Fineran Peter C. 
Published: September 2019

SUMMARYCRISPR-Cas systems provide bacteria with adaptive immunity against bacteriophages1. However, DNA modification2,3, the production of anti-CRISPR proteins4,5 and potentially other strategies enable phages to evade CRISPR-Cas. Here we discovered a Serratia jumbophage that evaded type I CRISPR-Cas systems, but was sensitive to type III immunity. Jumbophage infection resulted in a nucleus-like structure enclosed by a proteinaceous phage shell – a phenomenon only reported recently for distantly related Pseudomonas phages6,7. All three native CRISPR-Cas complexes in Serratia – type I-E, I-F and III-A – were spatially excluded from the phage nucleus and phage DNA was not targeted. However, the type III-A system still arrested jumbophage infection by targeting phage RNA in the cytoplasm in a process requiring Cas7, Cas10 and an accessory nuclease. Type III, but not type I, systems frequently targeted nucleus-forming jumbophages that were identified in global viral sequence datasets. These findings explain why many bacteria harbour both RNA- and DNA-targeting CRISPR-Cas systems1,8. Together, our results indicate that jumbophage nucleus-like compartments serve as a barrier to DNA-targeting, but not RNA-targeting defences, and that this phenomenon is widespread amongst jumbophages.
Gene-Gene interactions and pleiotropy in the brain nicotinic pathway associated with the heaviness and precocity of tobacco smoking among outpatients with multiple substance use disorders
Authors: Icick Romain , Besson Morgane , Zerdazi El-Hadi , Prince Nathalie , Bloch Vanessa , Laplanche Jean-Louis , Faure Philippe , Bellivier Frank , Maskos Uwe , Vorspan Florence 
Published: September 2019

AbstractIntroductionTobacco smoking is a major health burden worldwide, especially in populations suffering from other substance use disorders (SUDs). Several smoking phenotypes have been associated with single nucleotide polymorphisms (SNPs) of nicotinic acetylcholine receptors (nAChRs). Yet, little is known about the genetics of tobacco smoking in populations with other SUDs, particularly regarding gene-gene interactions and pleiotropy, which are likely involved in the polygenic architecture of SUDs. Thus, we undertook a candidate pathway association study of nAChR-related genes and smoking phenotypes in a sample of SUD patients.Methods493 patients with genetically-verified Caucasian ancestry were characterized extensively regarding patterns of tobacco smoking, other SUDs, and 83 SNPs from the nicotinic pathway, encompassing all brain nAChR subunits and metabolic/chaperone/trafficking proteins. Single-SNP, gene-based and SNP × SNP interactions analyses were performed to investigate associations with relevant tobacco smoking phenotypes. This included Bayesian analyses to detect pleiotropy, and adjustment on clinical and sociodemographic confounders.ResultsAfter multiple adjustment, we found independent associations between CHRNA3 rs8040868 and a higher number of cigarettes per day (CPD), and between RIC3 rs11826236 and a lower age at smoking initiation. Two SNP × SNP interactions were associated with age at onset (AAO) of daily smoking. There was pleiotropy regarding three SNPs in CHRNA3 (CPD, AAO daily smoking), ACHE (CPD, HSI) and CHRNB4 (CPD, both AAOs).DiscussionDespite limitations, the present study shows that the genetics of tobacco smoking in SUD patients are both distinct and partially shared across smoking phenotypes, and involve metabolic and chaperone effectors of the nicotinic pathway.
Dynamic perceptual feature selectivity in primary somatosensory cortex upon reversal learning
Authors: Chéreau Ronan , Bawa Tanika , Fodoulian Leon , Carleton Alan , Pagès Stéphane , Holtmaat Anthony 
Published: September 2019

ABSTRACTNeurons in primary sensory cortex encode a variety of stimulus features upon perceptual learning. However, it is unclear whether the acquired stimulus selectivity remains stable when the same input is perceived in a different context. Here, we monitored the activity of individual neurons in the mouse primary somatosensory cortex in a reward-based texture discrimination task. We tracked their stimulus selectivity before and after changing reward contingencies, which allowed us to identify various classes of neurons. We found neurons that stably represented a texture or the upcoming behavioral choice, but the majority was dynamic. Among those, a subpopulation of neurons regained selectivity contingent on stimulus-value. These value-sensitive neurons forecasted the onset of learning by displaying a distinct and transient increase in activity, depending on past behavioral experience. Thus, stimulus selectivity of excitatory neurons during perceptual learning is dynamic and largely relies on behavioral contingencies, even in primary sensory cortex.
Identifying differences in bile acid pathways for cholesterol clearance in Alzheimer’s disease using metabolic networks of human brain regions
Authors: Baloni Priyanka , Funk Cory C. , Yan Jingwen , Yurkovich James T. , Kueider-Paisley Alexandra , Nho Kwangsik , Heinken Almut , Jia Wei , Mahmoudiandehkordi Siamak , Louie Gregory , Saykin Andrew J. , Arnold Matthias , Kastenmüller Gabi , Griffiths William J , Thiele Ines ,   AMP-AD consortium,   The Alzheimer’s Disease Metabolomics Consortium, Kaddurah-Daouk Rima , Price Nathan D. 
Published: September 2019

AbstractAlzheimer’s disease (AD) is the leading cause of dementia, with metabolic dysfunction seen years before the emergence of clinical symptoms. Increasing evidence suggests a role for primary and secondary bile acids, the end-product of cholesterol metabolism, influencing pathophysiology in AD. In this study, we analyzed transcriptomes from 2114 post-mortem brain samples from three independent cohorts and identified that the genes involved in alternative bile acid synthesis pathway was expressed in brain compared to the classical pathway. These results were supported by targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals. We reconstructed brain region-specific metabolic networks using data from three independent cohorts to assess the role of bile acid metabolism in AD pathophysiology. Our metabolic network analysis suggested that taurine transport, bile acid synthesis and cholesterol metabolism differed in AD and cognitively normal individuals. Using the brain transcriptional regulatory network, we identified putative transcription factors regulating these metabolic genes and influencing altered metabolism in AD. Intriguingly, we find bile acids from the brain metabolomics whose synthesis cannot be explained by enzymes we find in the brain, suggesting they may originate from an external source such as the gut microbiome. These findings motivate further research into bile acid metabolism and transport in AD to elucidate their possible connection to cognitive decline.
High molecular weight DNA isolation method from diverse plant species for use with Oxford Nanopore sequencing
Authors: Vaillancourt Brieanne , Buell C. Robin 
Published: September 2019

AbstractThe ability to generate long reads on the Oxford Nanopore Technologies sequencing platform is dependent on the isolation of high molecular weight DNA free of impurities. For some taxa, this is relatively straightforward; however, for plants, the presence of cell walls and a diverse set of specialized metabolites such as lignin, phenolics, alkaloids, terpenes, and flavonoids present significant challenges in the generation of DNA suitable for production of long reads. Success in generating long read lengths and genome assemblies of plants has been reported using diverse DNA isolation methods, some of which were tailored to the target species and/or required extensive labor. To avoid the need to optimize DNA isolation for each species, we developed a taxa-independent DNA isolation method that is relatively simple and efficient. This method expands on the Oxford Nanopore Technologies high molecular weight genomic DNA protocol from plant leaves and utilizes a conventional cetyl trimethylammonium bromide extraction followed by removal of impurities and short DNA fragments using commercially available kits that yielded robust N50 read lengths and yield on Oxford Nanopore Technologies flow cells.
Neurodevelopmental wiring deficits in the Ts65Dn mouse model of Down syndrome
Authors: Jain Shruti , Watts Christina A. , Chung Wilson C.J. , Welshhans Kristy 
Published: September 2019

AbstractDown syndrome is the most common genetic cause of intellectual disability and occurs due to the trisomy of human chromosome 21. Adolescent and adult brains from humans with Down syndrome exhibit various neurological phenotypes including a reduction in the size of the corpus callosum, hippocampal commissure and anterior commissure. However, it is unclear when and how these interhemispheric connectivity defects arise. Using the Ts65Dn mouse model of Down syndrome, we examined interhemispheric connectivity in postnatal day 0 (P0) Ts65Dn mouse brains. We find that there is no change in the volume of the corpus callosum or anterior commissure in P0 Ts65Dn mice. However, the volume of the hippocampal commissure is significantly reduced in P0 Ts65Dn mice, and this may contribute to the impaired learning and memory phenotype of this disorder. Interhemispheric connectivity defects that arise during development may be due to disrupted axon growth. In line with this, we find that developing hippocampal neurons display reduced axon length in vitro, as compared to neurons from their euploid littermates. This study is the first to report the presence of defective interhemispheric connectivity at the time of birth in Ts65Dn mice, providing evidence that early therapeutic intervention may be an effective time window for the treatment of Down syndrome.
Robotic hand-arm system for on-orbit servicing missions in Tiangong-2 Space Laboratory
Authors: Liu Yiwei , Cui Shipeng , Liu Hong , Jin Minghe , Ni Fenglei , Li Zhiqi , Li Chongyang 
Published: September 2019

Purpose
The purpose of this study is to develop a robotic hand–arm system for on-orbit servicing missions at the Tiangong-2 (TG-2) Space Laboratory.

Design/methodology/approach
The hand–arm system is mainly composed of a lightweight arm, a dexterous hand, an electrical cabinet, a global camera, a hand–eye camera and some human–machine interfaces. The 6-DOF lightweight arm and the 15-DOF dexterous hand adopt the modular design philosophy that greatly reduces the design cycle and cost. To reduce the computational burden on the central controller and simplify system maintenance, an electrical system which has a hierarchical structure is introduced.

Findings
The prototypical operating experiments completed in TG-2 space laboratory demonstrate the performance of the hand–arm system and lay foundations for the future applications of space manipulators.

Originality/value
The main contributions of this paper are as follows a robotic hand–arm system which can perform on-orbit servicing missions such as grasping the electric drill, screwing the bolt, unscrewing J599 electrical connector has been developed; a variable time step motion plan method is proposed to adjust the trajectories of the lightweight arm to reduce or eliminate the collision force; and a dexterous hand uses the coordinated grasp control based on the object Cartesian stiffness to realize stable grasp. To solve the kinematic mapping from the cyber glove commands to the dexterous hand, a fingertip-position-based method is proposed to acquire precise solutions.
Design and human–machine compatibility analysis of Co-Exos II for upper-limb rehabilitation
Authors: Zhang Leiyu , Li Jianfeng , Ji Shuting , Su Peng , Tao Chunjing , Ji Run 
Published: September 2019

Purpose
Upper-limb joint kinematics are highly complex and the kinematics of rehabilitation exoskeletons fail to reproduce them, resulting in hyperstaticity and human–machine incompatibility. The purpose of this paper is to design and develop a compatible exoskeleton robot (Co-Exos II) to address these problems.

Design/methodology/approach
The configuration synthesis of Co-Exos II is completed using advanced mechanism theory. A compatible configuration is selected and four passive joints are introduced into the connecting interfaces based on optimal configuration principles. A Co-Exos II prototype with nine degrees of freedom (DOFs) is developed and still owns a compact structure and volume. A new approach is presented to compensate the vertical glenohumeral (GH) movements. Co-Exos II and the upper arm are simplified as a guide-bar mechanism at the elevating plane. The theoretical displacements of passive joints are calculated by the kinematic model of the shoulder loop. The compatible experiments are completed to measure the kinematics of passive joints.

Findings
The compatible configuration of the passive joints can effectively reduce the gravity influences of the exoskeleton device and the upper extremities. The passive joints exhibit excellent compensation effect for the GH joint movements by comparing the theoretical and measured results. Passive joints can compensate for most GH movements, especially vertical movements.

Originality/value
Co-Exos II possesses good human–machine compatibility and wearable comfort for the affected upper limbs. The proposed compensation method is convenient to therapists and stroke patients during the rehabilitation trainings.