bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery of isoplumbagin as a novel NQO1 substrate and anti-cancer quinone
Authors: Tsao Yen-Chi , Chang Yu-Jung , Wang Chun-Hsien , Chen Linyi 
Published: April 2020

AbstractIsoplumbagin (5-hydroxy-3-methyl-1,4-naphthoquinone), a naturally occurring quinone fromLawsonia inermisandPlumbago europaea, that has been reported to have anti-inflammatory and anti-microbial activity. Inflammation has long been implicated in cancer progression. In this study, we examined the anti-cancer effect of chemically-synthesized isoplumbagin. Our results revealed that isoplumbagin treatment suppressed cell viability and invasion of highly invasive oral squamous cell carcinoma (OSCC) OC3-IV2 cells, glioblastoma U87 cells, non-small cell lung carcinoma H1299 cells, prostate cancer PC3 cells, and cervical cancer Hela cells by using MTT and Boyden chamber assays.In vivostudies demonstrate the inhibitory effect of 2 mg/kg isoplumbagin on the growth of orthotopic xenograft tumors derived from OSCC cells. Mechanistically, isoplumbagin exerts its cytotoxic effect through acting as a substrate of NAD(P)H quinone dehydrogenase 1 (NQO1) to generate hydroquinone, which reverses mitochondrial fission phenotype, reduces mitochondrial complex IV activity and thus compromises mitochondrial function. Collectively, this work reveals an anti-cancer activity of isoplumbagin mainly through modulating mitochondrial dynamics and function.Chemical compounds:Isoplumbagin (PubChem CID: 375105)
The archives are half-empty: a field-wide assessment of the availability of microbial community sequencing data
Authors: Jurburg Stephanie D. , Konzack Maximilian , Eisenhauer Nico , Heintz-Buschart Anna 
Published: April 2020

AbstractThe sequencing revolution has resulted in the explosive growth of public genetic repositories. These repositories now hold invaluable collections of 16S rRNA gene amplicon sequences, but the extent to which the currently archived data is findable, accessible, and reusable has not been evaluated. We conducted a field-wide assessment of the availability and state of publicly archived 16S rRNA gene amplicon sequencing data. Using custom-built pattern-based text extraction algorithms, we searched 26,927 publications in 17 microbiology or microbial ecology journals, and identified 2,015 studies which performed 16S rRNA gene amplicon sequencing. We found, for example, that 7.2% of these had not been made public at the time of analysis, a trend which increased over time. Of the 635 studies targeting the V3-V4 region of the 16S rRNA gene, 40.3% contained data which was not available or not reusable, and for 25.5% of the studies, faults in data formatting or data labelling were likely to create obstacles in data reuse. Taken together, only 34% of these datasets had potentially reusable data. Our study reveals significant gaps in the availability of currently deposited community sequencing data, identifies major contributors to data loss, and offers suggestions for improving data archiving practices in the future.
[18F]DCP, First Generation PET Radiotracer for Diagnosis of Radiation Resistant Head and Neck Cancer
Authors: Chen Xiaofei , Sai Kiran Kumar Solingapuram , Li Zhe , Zhu Caigang , Shukla Kirtikar , Forshaw Tom E. , Wu Hanzhi , Vance Stephen A. , Madonna Megan , Dewhirst Mark W. , Tsang Allen W. , Poole Leslie B. , Ramanujam Nimmi , King S. Bruce , Furdui Cristina M. 
Published: April 2020

AbstractRedox metabolism plays essential functions in the pathology of cancer. As tumor redox profiles uniquely reflect cancer stage and in select cases, therapeutic sensitivity, the capability to image redox molecular features is essential to improve diagnosis, treatment, and overall quality-of-life (QOL) of cancer patients. While a number of radiotracers for imaging redox metabolism have been developed, there are no reports of radiotracers for in vivo imaging of protein oxidation. Here we take the first step towards this goal and describe the synthesis and kinetic properties of a new positron emission tomography (PET) [18F]DCP radiotracer for in vivo imaging of protein sulfenylation. Time course biodistribution and PET/CT studies using xenograft animal models of Head and Neck Squamous Cell Cancer (HNSCC) demonstrate feasibility of diagnosing radiation resistant tumors, which display lower [18F]DCP signal. These findings are consistent with our previous reports of decreased protein sulfenylation in clinical specimens of radiation resistant HNSCC. We anticipate further development and implementation of this concept in clinical practice to improve the diagnosis of patients with radiation resistant tumors and the accuracy of prognosis for patients undergoing radiation treatment.Single Sentence SummaryThe study introduces a new PET radiotracer for profiling tumor protein oxidation as a prognostic indicator of resistance to radiation therapy.
Associations Between Resting State Functional Connectivity and a Hierarchical Dimensional Structure of Psychopathology in Middle Childhood
Authors: Karcher Nicole R. , Michelini Giorgia , Kotov Roman , Barch Deanna M. 
Published: April 2020

AbstractBackgroundPrevious research from the Adolescent Brain Cognitive Development (ABCD) study delineated and validated a hierarchical 5-factor structure with a general psychopathology (‘p’) factor at the apex and five specific factors (internalizing, somatoform, detachment, neurodevelopmental, externalizing) using parent-reported child symptoms. The current study is the first examining associations between dimensions from a hierarchical structure and resting state functional connectivity (RSFC) networks.MethodsUsing 9-11-year-old children from the ABCD baseline sample, we compared the variance explained by each hierarchy level (p-factor, 2-factor, 3-factor, 4-factor, and 5-factor models) in RSFC. Analyses were first conducted in a discovery dataset (n=3790) with significant associations examined in a replication dataset (n=3791).ResultsThe current study found associations between p-factor and lower connectivity within default mode network (DMN), although stronger effects emerged for the neurodevelopmental factor. Neurodevelopmental impairments were related to variation in RSFC networks associated with attention to internal states and external stimuli. These networks included within DMN, DMN with cingulo-opercular (CON) and ‘Other’ (Unassigned) networks, CON with ventral attention and ‘Other’ network, and dorsal attention with ‘Other’ network. Results held when accounting for parental psychopathology.ConclusionThe hierarchical structure of psychopathology showed replicable links to RSFC alterations in middle childhood. The p-factor had minimal association with altered connectivity, while the specific neurodevelopmental dimension showed robust associations with multiple RSFC impairments. Results show the utility of examining associations between intrinsic brain architecture and specific dimensions of psychopathology, revealing associations specifically with neurodevelopmental impairments.
Serotonergic control in initiating defensive responses to unexpected tactile stimuli in the trap-jaw antOdontomachus kuroiwae
Authors: Aonuma Hitoshi 
Published: April 2020

ABSTRACTA decision to express a defensive response or an escape response to a potential threat is crucial for insects to survive. This study investigated an aminergic mechanism underlying defensive responses to unexpected touch in an ant that has powerful mandibles, the so-called trap-jaw. The mandibles close extremely quickly and are used as a weapon during hunting. Tactile stimulation to the abdomen elicited quick forward movements in a “dart escape” in 90% of the ants in a colony. Less than 10% of the ants responded with a quick “defensive turn” towards the source of stimulation. To reveal the neuronal control mechanisms underlying this defensive behavior, the effects of brain biogenic amines on the responses to tactile stimulus were investigated. The levels of octopamine (OA), dopamine (DA) and serotonin (5HT) in the brain were significantly elevated in ants that responded with a defensive turn to the unexpected stimulus compared to ants that responded with a dart escape. Oral administration of DA and 5HT demonstrated that both amines contributed to the initiation of a defensive response to the stimulus. Oral administration of L-DOPA weakly affected the initiation of the defensive turn, while 5HTP strongly affected the initiation of defensive behavior. Oral administration of an antagonist of 5HT, ketanserin, abolished the effect of 5HTP. These results indicate that endogenous 5HT in the brain has a key role to play in modulating the initiation of defensive behavior in the trap-jaw ant.
A Bayesian neural network for toxicity prediction
Authors: Semenova Elizaveta , Williams Dominic P. , Afzal Avid M. , Lazic Stanley E. 
Published: April 2020

AbstractPredicting the toxicity of a compound preclinically enables better decision making, thereby reducing development costs and increasing patient safety. It is a complex issue, butin vitroassays and physico-chemical properties of compounds can be used to predict clinical toxicity. Neural networks (NNs) are a popular predictive tool due to their flexibility and ability to model non-linearities, but they are prone to overfitting and therefore are not recommended for small data sets. Furthermore, they don’t quantify uncertainty in the predictions. Bayesian neural networks (BNNs) are able to avoid these pitfalls by using prior distributions on the parameters of a NN model and representing uncertainty about the predictions in the form of a distribution. We model the severity of drug-induced liver injury (DILI) to provide an example of a BNN performing better than a traditional but less flexible proportional odds logistic regression (POLR) model. We use appropriate metrics to evaluate predictions of the ordinal data type. To demonstrate the effect of a hierarchical prior for BNNs as an alternative to hyperparameter optimisation for NNs, we compare the performance of a BNN against NNs with dropout or penalty regularisation. We reduce the task to multiclass classification in order to be able to perform this comparison. A BNN trained for the multiclass classification produces poorer results than a BNN that captures the order. The current work lays a foundation for more complex models built on larger datasets, but can already be adopted by safety pharmacologists for risk quantification.
Gene duplication drives genome expansion in Thaumarchaeota
Authors: Sheridan Paul O. , Raguideau Sebastien , Quince Christopher ,   Thames Consortium, Williams Tom A. , Gubry-Rangin Cécile 
Published: April 2020

AbstractAmmonia-oxidising archaea of the phylum Thaumarchaeota are keystone species in global nitrogen cycling. However, only three of the six known families of the terrestrially ubiquitous order Nitrososphaerales possess representative genomes. Here we provide genomes for the three remaining families and examine the impact of gene duplication, loss and transfer events across the entire phylum. Much of the genomic divergence in this phylum is driven by gene duplication and loss, but we also detected early lateral gene transfer that introduced considerable proteome novelty. In particular, we identified two large gene transfer events into Nitrososphaerales. The fate of gene families originating on these branches was highly lineage-specific, being lost in some descendant lineages, but undergoing extensive duplication in others, suggesting niche-specific roles within soil and sediment environments. Overall, our results suggest that lateral gene transfer followed by gene duplication drives Nitrososphaerales evolution, highlighting a previously under-appreciated mechanism of genome expansion in archaea.
ST6GAL1-mediated heterogeneity in sialic acid levels potentiates invasion of breast cancer epithelia
Authors: Pally Dharma , Pramanik Durjay , Hussain Shahid , Verma Shreya , Srinivas Anagha , Kumar Rekha V , Bhat Ramray 
Published: April 2020

AbstractHeterogeneity in phenotypes of malignantly transformed cells and aberrant glycan expression on their surface are two prominent hallmarks of cancers that have hitherto not been linked to each other. In this paper, we identify heterogeneity in a specific glycan linkage: α2,6-linked sialic acids within breast cancer cellsin vivoand in culture. Upon sorting out two populations with moderate and relatively higher cell surface α2,6-linked sialic acid levels from the triple negative breast cancer cell line MDA-MB-231, both populations (denoted as medium and high-2,6-Sial cells respectively) stably retained their levels in early passages. Upon continuous culturing, medium 2,6-Sial cells recapitulated the heterogeneity of the unsorted line whereas high 2,6-Sial cells showed no such tendency. Compared with the high 2,6-Sial, the medium 2,6-Sial cells showed greater adhesion to reconstituted extracellular matrices (ECM) as well as invaded faster as single cells. The level of α2,6-linked sialic acids in the two sublines was found to be consistent with the expression of a specific glycosyl transferase,ST6GAL1. Stably knocking downST6GAL1in the high 2,6-Sial cells, enhanced their invasiveness. When cultured together, medium 2,6-Sial cells differentially migrated to the edge of growing tumoroid-like cultures, whereas high 2,6-Sial cells formed the central bulk. Simulations in a Cellular Potts model-based computational environment that is calibrated to our experimental findings suggest that the heterogeneity of cell-ECM adhesion, likely regulated by α2,6-linked sialic acids facilitates niches of highly invasive cells to efficiently migrate centrifugally as the invasive front of a malignant tumor.Significance StatementCell-surface sugars are aberrantly expressed in cancer but their contributions to tumor heterogeneity are not known. In this study, we uncover and separate breast cancer populations with distinct α2,6-linked sialic acid levels. The moderately expressing population shows stronger adhesion to extracellular matrix than the high expressing population. It also invades faster through the matrix as single cells. Combining experiments with computational modelling, we show that the heterogeneity in matrix adhesion is vital to accentuating cell invasion. In some conditions, invasion of heterogeneous populations may compare with, or exceed that of, homogeneous moderately expressing populations. Our findings are vital to furthering our understanding of how cancers spread and potentially qualify efforts to manage the disease through glycan-editing or immunotherapeutic approaches.
Collateral sensitivity interactions between antibiotics depend on local abiotic conditions
Authors: Allen Richard C. , Pfrunder-Cardozo Katia R. , Hall Alex R. 
Published: April 2020

AbstractMutations conferring resistance to one antibiotic can increase (cross resistance) or decrease (collateral sensitivity) resistance to others. Drug combinations displaying collateral sensitivity could be used in treatments that slow resistance evolution. However, lab-to-clinic translation requires understanding whether collateral effects are robust across different environmental conditions. Here, we isolated and characterized resistant mutants ofEscherichia coliusing five antibiotics, before measuring collateral effects on resistance to other antibiotics. During both isolation and phenotyping, we varied conditions in ways relevant in nature (pH, temperature, bile). This revealed local abiotic conditions modified expression of resistance against both the antibiotic used during isolation and other antibiotics. Consequently, local conditions influenced collateral sensitivity in two ways: by favouring different sets of mutants (with different collateral sensitivities), and by modifying expression of collateral effects for individual mutants. These results place collateral sensitivity in the context of environmental variation, with important implications for translation to real-world applications.
Functional and diffusion MRI reveal the functional and structural basis of infants’ noxious-evoked brain activity
Authors: Baxter Luke , Moultrie Fiona , Fitzgibbon Sean , Aspbury Marianne , Mansfield Roshni , Bastiani Matteo , Rogers Richard , Jbabdi Saad , Duff Eugene , Slater Rebeccah 
Published: April 2020

AbstractUnderstanding the neurophysiology underlying pain perception in infants is central to improving early life pain management. In this multimodal MRI study, we use resting-state functional and white matter diffusion MRI to investigate individual variability in infants’ noxious-evoked brain activity. In an 18-infant nociception-paradigm dataset, we show it is possible to predict infants’ cerebral haemodynamic responses to experimental noxious stimulation using their resting-state activity across nine networks from a separate stimulus-free scan. In an independent 215-infant Developing Human Connectome Project dataset, we use this resting-state-based prediction model to generate noxious responses. We identify a significant correlation between these predicted noxious responses and infants’ white matter mean diffusivity, and this relationship is subsequently confirmed within our nociception-paradigm dataset. These findings reveal that a newborn infant’s pain-related brain activity is tightly coupled to both their spontaneous resting-state activity and underlying white matter microstructure. This work provides proof-of-concept that knowledge of an infant’s functional and structural brain architecture could be used to predict pain responses, informing infant pain management strategies and facilitating evidence-based personalisation of care.
Effect of MIND Diet Intervention on Cognitive Performance and Brain Structure in Healthy Obese Women: A Randomized Controlled Trial
Authors: Arjmand Golnaz , Abbas-Zadeh Mojtaba , Eftekhari Mohammad Hassan 
Published: April 2020

AbstractBackground and AimPrevious studies suggested adherence to recently developed Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) associated with cognitive performance. There was no prior Randomized controlled Trial (RCT) to investigate this association. This study aimed to examine the effect of MIND dietary pattern on features of cognitive performance and also changes in brain structure in healthy obese women.MethodsAs a total of 50 obese women assessed for eligibility, we randomly allocated 40 participants with mean BMI 32 ± 4.31 and mean age 48 ± 5.38 years to either calorie-restricted modified MIND diet or a calorie-restricted standard control diet. Change in cognitive performance was the primary outcome measured with a comprehensive neuropsychological test battery. We also performed voxel-based morphometry as a secondary outcome to quantify the differences in brain structure. All of the measurements administered at baseline and three months follow up.ResultsThirty-seven participants (MIND group=22 and control group=15) completed the study. The results found in the MIND diet group working memory +1.37 (95% CI: 0.79,1.95), verbal recognition memory +4.85 (95% CI: 3.30,6.40), and attention +3.75 (95% CI: 2.43,5.07) improved more compared with the control group (ps< 0.05). Results of brain MRI consists of an increase in surface area of inferior frontal gyrus in the MIND diet group. Furthermore, the results showed a decrease in the cerebellum-white matter and cerebellum-cortex in two groups of study. Still, the effect in the MIND group was greater than the control group.ConclusionsThe study findings declare for the first time that the MIND diet intervention can reverse the destructive effects of obesity on cognition and brain structure, which could be strengthened by a modest calorie restriction.
The E3 ubiquitin-protein ligase MDM2 is a novel interactor of the von Hippel-Lindau tumor suppressor
Authors: Falconieri Antonella , Minervini Giovanni , Bortolotto Raissa , Piovesan Damiano , Lopreiato Raffaele , Sartori Geppo , Pennuto Maria , Tosatto Silvio C.E. 
Published: April 2020

AbstractMutations of the von Hippel-Lindau (pVHL) tumor suppressor are causative of a familiar predisposition to develop different types of cancer. pVHL is mainly known for its role in regulating hypoxia-inducible factor 1-α (HIF-1α) degradation, thus modulating the hypoxia response. There are different pVHL isoforms, including pVHL30 and pVHL19. However, little is known about isoform-specific functions and protein-protein interactions. Integratingin silicopredictions within vitroand invivoassays, we describe a novel interaction between pVHL and mouse double minute 2 homolog (MDM2). Importantly, we found that pVHL30, and not pVHL19, forms a complex with MDM2, and that the N-terminal acidic tail of pVHL30 is required for its association with MDM2. Further, we demonstrate that an intrinsically disordered region upstream of the tetramerization domain of MDM2 is responsible for its isoform-specific association with pVHL30. This region is highly conserved in higher mammals, including primates, similarly to what has been already proposed for the N-terminal tail of pVHL30. Finally, we show that overexpression of pVHL30 and MDM2 together reduces cell proliferation, suggesting a synergistic effect of these E3 ubiquitin ligases. Collectively, our data support the idea that pVHL30 plays a role in MDM2 regulation, suggesting a wider interplay among hypoxia sensing and cell cycle regulation.
Inhibition of HIV-1 gene transcription by KAP1 in myeloid lineage
Authors: Ait Ammar Amina , Bellefroid Maxime , Daouad Fadoua , Martinelli Valérie , Van Assche Jeanne , Wallet Clémentine , De Rovere Marco , Fahrenkrog Birthe , Schwartz Christian , Van Lint Carine , Gautier Virginie , Rohr Olivier 
Published: April 2020

ABSTRACTHIV-1 latency generates reservoirs that prevent viral eradication by the current therapies. To find strategies toward an HIV cure, detailed understandings of the molecular mechanisms underlying establishment and persistence of the reservoirs are needed. The cellular transcription factor KAP1 is known as a potent repressor of gene transcription. Here we report that KAP1 represses HIV-1 gene expression in myeloid cells including microglial cells, the major reservoir of the central nervous system. Mechanistically, KAP1 interacts and colocalizes with the viral transactivator Tat to promote its degradation via the proteasome pathway and repress HIV-1 gene expression. In myeloid models of latent HIV-1 infection, the depletion of KAP1 increased viral gene elongation and reactivated HIV-1 expression. Bound to the latent HIV-1 promoter, KAP1 associates and cooperates with CTIP2, a key epigenetic silencer of HIV-1 expression in microglial cells. In addition, Tat and CTIP2 compete for KAP1 binding suggesting a dynamic modulation of the KAP1 cellular partners upon HIV-1 infection. Altogether, our results suggest that KAP1 contributes to the establishment and the persistence of HIV-1 latency in myeloid cells.