bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain source imaging based on movement-related cortical potentials induced by fatigue during self-paced handgrip contractions
Authors: Guo Feng , Zhang Tianyu , Hanson Nicholas J. , Zhang Rihui 
Published: January 2020

Purpose
By using standard low resolution electromagnetic tomography (sLORETA), we sought to explore the changes in brain source localization when performing right handgrip contractions in the condition of muscular fatigue.

Methods
Ten healthy adults volunteered for this study, and were asked to perform repeated and intermittent self-paced right handgrip contractions at 30% maximal voluntary contraction based on visual feedback leading to fatigue of right flexor digitorum profundus. Motor potentials from the movement-related cortical potentials were extracted from the electroencephalogram and were further analyzed by sLORETA.

Results
The activated cortical regions were mainly the Brodmann area 6 on the superior frontal and medial frontal gyri, and the BA 10 on the frontal and medial frontal gyri. With the development of muscular fatigue, current density of the motor potential significantly increased and the activated cortical areas markedly enlarged.

Conclusion
In an attempt to maintain a target level of force during upper limb muscle fatigue induced by low intensity repetitive activation, the brain enhances the activation of sensorimotor cortex and enlarges the sensorimotor cortex area, especially in the ipsilateral hemisphere.
A translational kidney organoid system bolsters human relevance of clinical development candidate
Authors: Westerling-Bui Amy , Soare Thomas W. , Venkatachalan Srinivasan , DeRan Michael , Fast Eva Maria , Fanelli Alyssa B. , Kyrychenko Sergii , Hoang Hien , Corriea Grinal M. , Zhang Wei , Yu Maolin , Daniels Matthew , Malojcic Goran , Pan-Zhou Xin-Ru , Ledeboer Mark W. , Harmange Jean-Christophe , Emani Maheswarareddy , Tibbitts Thomas T. , Reilly John F. , Mundel Peter 
Published: January 2020

AbstractA major challenge in drug discovery is gaining confidence in the human relevance of pre-clinical animal studies. While human iPSC-derived organoids offer exciting opportunities to address this, concerns about applicability and scalability remain. Here, we report a high-throughput organoid platform for assessment of kidney disease targeting compounds in a human system. We confirmed platform reproducibility by single cell RNA-Seq (scRNA-Seq) and derived a NanoString panel for efficient quality control (QC). Organoid transplantation in rats for 2 to 4 weeks promoted organoid maturation and vascularization. In functional studies, cyclosporine A (CsA) and GFB-887, a novel TRPC5 channel blocker, protected kidney organoids from injury. Pharmacodynamic studies with GFB-887 delivered orally to rats were also successfully performed in human transplanted organoids. These data show how human organoids can deliver confidence in taking development candidate compounds to the clinic, fulfilling their promise to revolutionize drug discovery.
MONN: a Multi-Objective Neural Network for Predicting Pairwise Non-Covalent Interactions and Binding Affinities between Compounds and Proteins
Authors: Li Shuya , Wan Fangping , Shu Hantao , Jiang Tao , Zhao Dan , Zeng Jianyang 
Published: January 2020

AbstractComputational approaches for inferring the mechanisms of compound-protein interactions (CPIs) can greatly facilitate drug development. Recently, although a number of deep learning based methods have been proposed to predict binding affinities and attempt to capture local interaction sites in compounds and proteins through neural attentions, they still lack a systematic evaluation on the interpretability of the identified local features. In addition, in these previous approaches, the exact matchings between interaction sites from compounds and proteins, which are generally important for understanding drug mechanisms of action, still remain unknown. Here, we compiled the first benchmark dataset containing the inter-molecular non-covalent interactions for more than 10,000 compound-protein pairs, and used it to systematically evaluate the interpretability of neural attentions in existing prediction models. We developed a multi-objective neural network, called MONN, to predict both non-covalent interactions and binding affinity for a given compound-protein pair. MONN uses convolution neural networks on molecular graphs of compounds and primary sequences of proteins to effectively capture the intrinsic features from both inputs, and also takes advantage of the predicted non-covalent interactions to further boost the accuracy of binding affinity prediction. Comprehensive evaluation demonstrated that while the previous neural attention based approaches fail to exhibit satisfactory interpretability results without extra supervision, MONN can successfully predict non-covalent interactions on our benchmark dataset as well as another independent dataset derived from the Protein Data Bank (PDB). Moreover, MONN can outperform other state-of-the-art methods in predicting compound-protein binding affinities. In addition, the pairwise interactions predicted by MONN displayed compatible and accordant patterns in chemical properties, which provided another evidence to support the strong predictive power of MONN. These results suggested that MONN can offer a powerful tool in predicting binding affinities of compound-protein pairs and also provide useful insights into understanding the molecular mechanisms of compound-protein interactions, which thus can greatly advance the drug discovery process. The source code of the MONN model and the dataset creation process can be downloaded fromhttps://github.com/lishuya17/MONN.
Single cell epigenomic atlas of the developing human brain and organoids
Authors: Ziffra Ryan S. , Kim Chang N. , Wilfert Amy , Turner Tychele N. , Haeussler Maximilian , Casella Alex M. , Przytycki Pawel F. , Kreimer Anat , Pollard Katherine S. , Ament Seth A. , Eichler Evan E. , Ahituv Nadav , Nowakowski Tomasz J. 
Published: January 2020

AbstractDynamic changes in chromatin accessibility coincide with important aspects of neuronal differentiation, such as fate specification and arealization and confer cell type-specific associations to neurodevelopmental disorders. However, studies of the epigenomic landscape of the developing human brain have yet to be performed at single-cell resolution. Here, we profiled chromatin accessibility of >75,000 cells from eight distinct areas of developing human forebrain using single cell ATAC-seq (scATACseq). We identified thousands of loci that undergo extensive cell type-specific changes in accessibility during corticogenesis. Chromatin state profiling also reveals novel distinctions between neural progenitor cells from different cortical areas not seen in transcriptomic profiles and suggests a role for retinoic acid signaling in cortical arealization. Comparison of the cell type-specific chromatin landscape of cerebral organoids to primary developing cortex found that organoids establish broad cell type-specific enhancer accessibility patterns similar to the developing cortex, but lack many putative regulatory elements identified in homologous primary cell types. Together, our results reveal the important contribution of chromatin state to the emerging patterns of cell type diversity and cell fate specification and provide a blueprint for evaluating the fidelity and robustness of cerebral organoids as a model for cortical development.
Regulation of Prefrontal Patterning, Connectivity and Synaptogenesis by Retinoic Acid
Authors: Shibata Mikihito , Pattabiraman Kartik , Lorente-Galdos Belen , Andrijevic David , Xing Xiaojun , Sousa Andre M. M. , Santpere Gabriel , Sestan Nenad 
Published: January 2020

AbstractThe prefrontal cortex (PFC) and its reciprocal connections with the mediodorsal thalamus (MD) are crucial for cognitive flexibility and working memory1–4and are thought to be altered in several disorders such as autism spectrum disorder5, 6and schizophrenia6–9. While developmental mechanisms governing regional patterning of the rodent cerebral cortex have been characterized10–15, the mechanisms underlying the development of PFC-MD connectivity and the lateral expansion of PFC with distinct granular layer 4 in anthropoid primates16–23have not been elucidated. Here we report increased concentration of retinoic acid (RA), a signaling molecule involved in brain development and function24, 25in the prospective PFC areas of human and macaque, compared to mouse, during mid-fetal development, a crucial period for cortical circuit assembly. In addition, we observed the lateral expansion of RA synthesizing enzyme, ALDH1A3, expression in mid-fetal macaque and human frontal cortex, compared to mouse. Furthermore, we found that enrichment of RA signaling is restricted to the prospective PFC byCYP26B1, a gene encoding an RA-catabolizing enzyme upregulated in the mid-fetal motor cortex. Gene deletion in mice revealed that RA signaling through anteriorly upregulated RA receptors,RxrgandRarb, andCyp26b1-dependent catabolism is required for the proper molecular patterning of PFC and motor areas, the expression of the layer 4 markerRORB, intra-PFC synaptogenesis, and the development of reciprocal PFC-MD connectivity. Together, these findings reveal a critical role for RA signaling in PFC development and, potentially, its evolutionary expansion.
Hominini-Specific Regulation ofCBLN2Increases Prefrontal Synaptogenesis
Authors: Shibata Mikihito , Pattabiraman Kartik , Muchnik Sydney K. , Sestan Nenad 
Published: January 2020

AbstractThe similarities and differences between nervous systems of various species result from developmental constraints and specific adaptations1-4. Comparative analyses of the prefrontal cortex (PFC), a region of the cerebral cortex involved in higher-order cognition and complex social behaviors, have identified confirmed and putative human-specific structural and molecular changes4-8. For example, one crucial specialization involves the anterior-posterior gradient in synaptic density, with a disproportionately higher number of dendritic spines specifically in the human PFC compared to other analyzed primates5. These changes are likely mediated by divergence in spatio-temporal patterns of gene expression9-17, which are prominent in the mid-fetal human cerebral neocortex15,18-20. Analyzing developmental human and macaque brain transcriptomic data15,20, we identified a transient PFC- and laminar-specific upregulation of the gene encoding cerebellin 2 (CBLN2), a neurexin (NRXN) and glutamate receptor delta (GRID/GluD)-associated synaptic organizer21-27, in human mid-fetal development coinciding with the initiation of synaptogenesis. Moreover, we show that this difference in expression level and laminar distribution ofCBLN2, is due to Hominini-specific deletions affecting SOX5 binding sites within a retinoic acid-responsiveCBLN2enhancer.In situgenetic humanization of the mouseCbln2enhancer drives increased and ectopic laminarCbln2expression and promotes glutamatergic and GABAergic synaptogenesis specifically in the PFC. These findings identify a putative genetic and molecular basis for the disproportionately increased connectivity in the Hominini PFC and suggest a developmental mechanism linking dysfunction of the NRXN-GRID-CBLN2 complex, to the pathogenesis of neuropsychiatric disorders.
Acetylation is required for NLRP3 self-aggregation and full activation of the inflammasome
Authors: Zhao Kai , Zhang Yening , Xu Xueming , Liu Liping , Huang Lingmin , Luo Ruiheng , Li Jing , Zhang Ningjie , Lu Ben 
Published: January 2020

AbstractThe full activation of NLRP3 inflammasome needs two sequential signals: the fist priming signal and the second assembly signal. Various stimuli including infections and stress signals can provide the assembly signal. However, how NLRP3 detects diverse stimuli and becomes fully activated remain largely unknown. In this study, we found the second signal specially triggers the acetylation of NLRP3, which facilitates the aggregation of NLRP3 and its interaction with ASC and NEK7, thus promoting the assembly of inflammasome. Meanwhile, by employing pharmacological and molecular approaches, we identified KAT5 as a regulator of NLRP3 acetylation and activation. Furthermore, KAT5 specific inhibitor-NU9056 exhibited a robust suppressive effect on NLRP3 inflammasome bothin vitroandin vivo. Thus, our study reveals a new mechanism for NLRP3 full activation and suggests targeting NLRP3 acetylation may provide a new approach for treatment of NLRP3 associated diseases.
Determinants of growth and body size inAustrolebiasSouth-American annual killifish
Authors: Helmstetter Andrew , Van Dooren Tom JM 
Published: January 2020

AbstractPatterns of size variation in fish are supposed to be generated by growth differences, not by egg or hatchling size variation. However, annual killifish live in temporary ponds with a limited time period available for growth and reproduction. It has therefore been hypothesized that among annual killifish, hatchling size variation should be of large relative importance to generate adaptive adult size variation. Using growth curves of 203 individuals from 18Austrolebiasspecies raised in a common environment, we demonstrate that hatchling size variation indeed is a main determinant of adult size variation in annual killifish, in agreement with the time constraint hypothesis. Furthermore, we find an increased early growth rate in piscivorous species augmenting their difference in size from small congeneric species. This should be adaptive if size differences determine predation success. Environmental effects of spatial location of the population of origin on hatchling size and growth suggest that the time constraint might be weakened in populations occurring near the Atlantic coast. Our study reveals how extreme environments demand specific life history solutions to achieve adaptive size variation and that there might be scope for local adaptations in growth trajectories.
Endothelial JAK2V617F mutation leads to thrombosis, vasculopathy, and cardiomyopathy in a murine model of myeloproliferative neoplasm
Authors: Castiglione Melissa , Mazzeo Christopher , Jiang Ya-Ping , Chen Juei-Suei , Kaushansky Kenneth , Yin Wei , Lin Richard Z. , Zheng Haoyi , Zhan Huichun 
Published: January 2020

ABSTRACTRationalThe myeloproliferative neoplasms (MPNs) are clonal hematological malignancies characterized by hematopoietic stem cell expansion and overproduction of mature blood cells. Cardiovascular complications are the leading cause of morbidity and mortality in patients with MPNs. The acquired kinase mutation JAK2V617F plays a central role in these disorders. Mechanisms responsible for cardiovascular dysfunction in MPNs are not fully understood, limiting the effectiveness of current treatment.ObjectiveVascular endothelial cells (ECs) play critical roles in the regulation of hemostasis and thrombosis. ECs carrying the JAK2V617F mutation can be detected in patients with MPNs. The goal of this study was to test the hypothesis that the JAK2V617F mutation alters endothelial function to promote cardiovascular complications in patients with MPNs.Methods and ResultsWe employed murine models of MPN in which the JAK2V617F mutation is expressed in specific cell lineages. When JAK2V617F is expressed in both blood cells and vascular ECs, the mice developed MPN and spontaneous, age-related dilated cardiomyopathy with an increased risk of sudden death as well as a prothrombotic and vasculopathy phenotype on histology evaluation. We showed that JAK2V617F-mutant ECs are required for this cardiovascular disease phenotype and the mutation can alter endothelial cell function. Finally, in a more therapeutically oriented approach, we demonstrated that transplantation with wild-type donor marrow cells can improve cardiac function by reversing the left ventricle remodeling process in this JAK2V617F-positive MPN murine model.ConclusionsThese findings suggest that the JAK2V617F mutation alters vascular endothelial function to promote cardiovascular complications in MPNs. Therefore, targeting the MPN vasculature represents a promising new therapeutic strategy for patients with MPNs.
Increased urocortin 3 levels are associated with the risk of having type 2 diabetes mellitus
Authors: Alarslan Pınar , Unal Kocabas Gokcen , Demir Ismail , Guler Aslı , Bozkaya Giray , Aslanipour Behnaz , Calan Mehmet 
Published: January 2020

AbstractBackgroundUrocortin 3 (UCN3) is a peptide hormone playing a pivotal role in glucose and lipid metabolisms. However, its clinical implications remain unclear. Our aims were to investigate the altered levels of UCN3 in newly diagnosed type 2 diabetes mellitus (nT2DM) patients in comparison to subjects with normal glucose tolerance (NGT) and to determine the presence of any possible link between UCN3 levels and metabolic parameters.MethodsEighty nT2DM and 80 age‐, body mass index (BMI)‐, and gender‐matched NGT subjects were enrolled into this case‐control study. The circulating UCN3 levels were measured using the enzyme‐linked immunoabsorbent assay (ELISA). Metabolic parameters of enrolled subjects were also determined. A standard 75‐g 2‐hour oral glucose tolerance test was used for diagnosis of type 2 diabetes mellitus (T2DM).ResultsUCN3 levels were higher in subjects with nT2DM than in controls (115.64 ± 39.26 vs 86.16 ± 22.81 pg/mL, P < .001). UCN3 levels were increased in subjects with metabolic syndrome compared to subjects without metabolic syndrome in both nT2DM and NGT groups. UCN3 levels showed a positive correlation with BMI in both groups. Moreover, UCN3 levels were positively and independently associated with insulin, fasting blood glucose, insulin resistance, 2‐hour plasma glucose, glycosylated hemoglobin, and triglycerides, whereas UCN3 levels were negatively and independently associated with high‐density lipoprotein cholesterol. According to logistic regression analysis, increased risk of T2DM and metabolic syndrome were parallel with the highest elevated levels of UCN3.ConclusionsIncreased levels of UCN3 are associated with unfavorable metabolic profiles in T2DM, indicating a potential role of UCN3 in glucose and lipid metabolisms in T2DM.
Effects of regional economics on the online sale of protected parrots and turtles in China
Authors: Ye Yun‐Chun , Yu Wen‐Hua , Newman Chris , Buesching Christina D. , Xu Ya‐li , Xiao Xiao , Macdonald David W. , Zhou Zhao‐Min 
Published: January 2020

AbstractThe sale of wild animals, including protected species, may relate to regional differences in socio‐politics, culture, and economic development. A better understanding of how these factors affect the illegal wildlife trade is therefore necessary to optimize the deployment of conservation resources and policing. To evaluate these factors in relation to the trade‐in protected animals as pets, we surveyed China's popular consumer‐to‐consumer website, Taobao.com (analogous to eBay), and found that over 70,000 individual live parrots and turtles (totaling 46 and 49 protected species, respectively) were sold in just 150 days. Using analyses that attempted to account for species richness estimation and autocorrelation effects, we identified that regional economics promoted the occurrence and extent of pet sales. The provenance of these traded animals was ambiguous, but their vast numbers raise two concerns: if any proportion was sourced illegally from the wild, it is of conservation concern; whereas any bred illegally in captivity raise animal welfare concerns, because this would be unregulated. In the context of rapid economic development in China, it is thus important to reform the legislation that currently allows these commonly traded pet species to slip through the net intended to police animal welfare and illegal animal trading.
Laboratory Technician Assessment of the Quality of Single‐Unit Crown Preparations and Impressions as Predictors of the Clinical Acceptability of Crowns as Determined by the Treating Dentist: Findings from the National Dental Practice‐Based Research Network
Authors: McCracken Michael S. , Litaker Mark S. , Thomson Alexandra E. S. , Slootsky Alan , Gilbert Gregg H. ,   National Dental PBRN Collaborative Group
Published: January 2020

AbstractPurposeIn‐laboratory assessment by laboratory technicians may offer insight to increase clinical success of dental crowns, and research in this area is lacking.Materials and MethodsDentists in the National Dental Practice‐Based Research Network enrolled patients in a study about single‐unit crowns; laboratory technicians evaluated the quality of tooth preparations and impressions. The primary outcome for each crown was clinical acceptability (CAC), as judged by the treating dentist. A secondary outcome was “Goodness of Fit (GOF),” a composite score of several aspects of clinical fit, also judged by the study dentist. A mixed‐effects logistic regression was used to analyze associations between laboratory technician ratings and the CAC and GOF.ResultsDentists (n = 205) evaluated 3731 crowns. Technicians ranked the marginal detail of impressions as good or excellent in 92% of cases; other aspects of the impression were ranked good or excellent 88% of the time. Regarding tooth preparation, about 90% of preparations were considered adequate (neither excessive nor inadequate reduction). Factors associated with higher CAC were more preparation taper, and use of optical imaging. Factors associated with better GOF were higher impression quality, greater occlusal reduction, more preparation taper, and optical imaging.ConclusionsOverall quality of preparations and impressions was very high, as evaluated by laboratory technicians. Several clinical parameters were associated with higher CAC and GOF. Clinicians who struggle with crown remakes might consider less conservative tooth preparation, as well as using digital impression technology.
Fadas em ação: uma breve análise da narrativa “O corvo”, de Ana de Castro Osório
Authors: Araújo Priscila Clementino Bezerra de , Santos Rita De Cássia Silva Dionísio 
Published: January 2020

OSÓRIO, Ana de Castro. O Corvo. In: Contos Tradicionais Portugueses para as Crianças. Lisboa: Instituto Piaget, 1997.
Beyond the NCCN Risk Factors in Colon Cancer: An Evaluation in a Swedish Population-Based Cohort
Authors: Osterman Erik , Mezheyeuski Artur , Sjöblom Tobias , Glimelius Bengt 
Published: January 2020

Abstract
Background
The purpose of this study was to investigate whether pT3–4 and pN-subclassifications, lymph-node ratio (LNR), tumour deposits, pre- and postoperative carcinoembryonic antigen (CEA), and C-reactive protein (CRP)—all parameters commonly collected in clinical management—add information about recurrence risk against a background of routine clinicopathological parameters as defined by the NCCN.

Methods
The prospective cohort consisted of all 416 patients diagnosed with colon cancer stage I–III in Uppsala County between 2010 and 2015. Cox proportional hazard models were used to calculate hazard ratios for time to recurrence and overall survival. The results were compared with the entire Swedish population concerning parameters recorded in the national quality registry, SCRCR, during the same time period.

Results
The Uppsala cohort was representative of the entire Swedish cohort. In unadjusted analyses, pT3-subclassification, pN-subclassification, LNR, tumour deposits, elevated postoperative CEA, and preoperative CRP correlated with recurrence. After adjusting for T-, N-stage, and NCCN risk factors, pN-subclassification, sidedness, and elevated postoperative CEA levels correlated with recurrence. Survival correlated with parameters associated with recurrence, LNR, and elevated postoperative CRP.

Conclusions
Additional information on recurrence risk is available from several routinely recorded parameters, but most of the risk is predicted by the commonly used clinicopathological parameters.