bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploration of interaction scoring criteria in the CANDO platform
Authors: Falls Zackary , Mangione William , Schuler James , Samudrala Ram 
Published: March 2019

AbstractBackgroundDrug discovery is an arduous process that requires many years and billions of dollars before approval for patient use. However, there are a number of drugs and human ingestibles approved for a variety of indications/diseases that can be potentially repurposed as new treatments for others, decreasing the time and cost required.MethodsCANDO (Computational Analysis of Novel Drug Opportunities) is a platform for shotgun, multitarget drug discovery and repurposing. The CANDO platform scores interactions between 46,784 proteins structures and 3,733 human use compounds using a bioinformatic docking protocol to generate compound-proteome interaction signatures that are then compared to identify candidates for repurposing. Benchmarking of the platform is accomplished by comparing the compound-proteome interaction signatures and determining whether signatures corresponding to pairs of drugs approved for the same indication fall within particular cutoffs.ResultsWe have altered the scoring function of bioinformatic docking protocol in the newest version of our platform (v1.5) to use the best OBscore for each compound-protein interaction, resulting in an increased benchmarking accuracy from 11.7% in v1 to 12.8% in v1.5 for the top10 cutoff, the most stringent one used, and correspondingly from 24.9% to 31.2% for the top100 cutoff.ConclusionsThe change in the interaction scoring and other bug fixes in CANDO v1.5 have resulted in improved benchmarking performance, making the platform more effective at predicting novel, therapeutic drug-indication pairs.
Exposure to maternal obesityper seprograms sex-differences in pancreatic islets of the offspring
Authors: Nicholas L M , Nagao M , Kusinski L C , Fernandez-Twinn D S , Eliasson L , Ozanne S E 
Published: March 2019

SummaryMaternal obesity increases type 2 diabetes (T2D) risk in the offspring. Given that nearly half of women of child-bearing age in many populations are currently overweight/obese, it is key that we improve our understanding of the impact of thein utero/early life environment on offspring islet function. Using a well-established mouse model of diet-induced obesity, we examined offspring islets before the onset of metabolic dysfunction. This allowed us to determine inherent changes, in males and females, which are distinct from the response of islets to an existing obesogenic, insulin resistant milieu hence identifying islet dysregulation reflecting very early manifestation of the disease before the onset of disrupted glucose homeostasis. Female offspring of obese dams displayed higher glucose-stimulated insulin secretion and mitochondrial respiration, increased expression of estrogen receptor α and decreased cleaved-caspase 3 and Bax:Bcl-2 reflecting reduced susceptibility to apoptosis. In contrast, male offspring of obese dams displayed compromised mitochondrial respiration characterised by decreased ATP synthesis-driven respiration and increased “uncoupled” respiration and reduced docked insulin granules in β-cells. Thus, maternal obesity “programs” sex-differences in offspring islet function. Islets of female but not male offspring appear primed to cope with a nutritionally-rich postnatal environment, which may reflect differences in future T2D risk.
Chitosan films for microfluidic studies of single bacteria and perspectives for antibiotics susceptibility testing
Authors: Tréguier Julie , Bugnicourt Loic , Gay Guillaume , Diallo Mamoudou , Islam Salim , Toro Alexandre , David Laurent , Théodoly Olivier , Sudre Guillaume , Mignot Tâm 
Published: March 2019

AbstractSingle cell microfluidics is powerful to study bacteria and determine their susceptibility to antibiotics treatment. Glass treatment by adhesive molecules is a potential solution to immobilize bacterial cells and perform microscopy but traditional cationic polymers such as poly-lysine deeply affect bacterial physiology. In this work, we chemically characterized a class of chitosan polymers for their biocompatibility when adsorbed to glass. Chitosan chains of known length and composition allowed growth of Escherichia coli cells without any deleterious effects on cell physiology. Combined with a machine-learning approach, this method could measure the antibiotics susceptibility of a diversity of clinical strains in less than 1 hour and with higher accuracy than current methods. Last, chitosan polymers also supported growth of Klebsiella pneumoniae, another bacterial pathogen of clinical significance. The low cost of chitosan slides and their simple implementation makes them highly versatile for research as well as clinical use.
Human influences on antipredator behaviour in Darwin’s finches
Authors: Gotanda Kiyoko M. 
Published: March 2019

Abstract1) Humans exert dramatic influences upon the environment, creating novel selective pressures to which organisms must adapt. On the Galapagos, humans have established a permanent presence and have altered selective pressures through influences such as invasive predators and urbanization, affecting iconic species such as Darwin’s finches.2) Here, I ask two key questions: (i) does antipredator behaviour (e.g. FID) change depending on whether invasive predators are historically absent, present, or eradicated? and (ii) to what degree does urbanization affect antipredator behaviour? This study is one of the first to quantify antipredator behaviour in endemic species after the eradication of invasive predators. This will help to understand the consequences of invasive predator eradication and inform conservation measures.3) I quantified flight initiation distance (FID), an antipredator behaviour, in Darwin’s finches, across multiple islands in the Galapagos that varied in the presence, absence, or successful eradication of invasive predators. On islands with human populations, I quantified FID in urban and non-urban populations of finches.4) FID was higher on islands with invasive predators compared to islands with no predators. On islands from which invasive predators were eradicated ∼11 years previously, FID was also higher than on islands with no invasive predators. Within islands that had both urban and non-urban populations of finches, FID was lower in urban finch populations, but only above a threshold human population size. FID in larger urban areas on islands with invasive predators was similar to or lower than FID on islands with no history of invasive predators.5) Overall, these results suggest that invasive predators can have a lasting effect on antipredator behaviour, even after eradication. Furthermore, the effect of urbanization can strongly oppose the effect of invasive predators, reducing antipredator behaviour to levels lower than found on pristine islands with no human influences. These results improve our understanding of human influences on antipredator behaviour which can help inform future conservation and management efforts on islands.
A Cas9 nanoparticle system with truncated Cas9 target sequences on DNA repair templates enhances genome targeting in diverse human immune cell types
Authors: Nguyen David N. , Roth Theodore L. , Li Jonathan , Chen Peixin Amy , Mamedov Murad R. , Vo Linda T. , Tobin Victoria , Apathy Ryan , Goodman Daniel , Shifrut Eric , Bluestone Jeffrey A. , Puck Jennifer M. , Szoka Francis C. , Marson Alexander 
Published: March 2019

ABSTRACTVirus-modified T cells are approved for cancer immunotherapy, but more versatile and precise genome modifications are needed for a wider range of adoptive cellular therapies1–4. We recently developed a non-viral CRISPR–Cas9 system for genomic site-specific integration of large DNA sequences in primary human T cells5. Here, we report two key improvements for efficiency and viability in an expanded variety of clinically-relevant primary cell types. We discovered that addition of truncated Cas9 target sequences (tCTS) at the ends of the homology directed repair (HDR) templates can interact with Cas9 ribonucleoproteins (RNPs) to ‘shuttle’ the template and enhance targeting efficiency. Further, stabilizing the Cas9 RNPs into nanoparticles with poly(glutamic acid) improved editing, reduced toxicity, and enabled lyophilized storage without loss of activity. Combining the tCTS HDR template modifications with polymer-stabilized nanoparticles increased gene targeting efficiency and viable cell yield across multiple genomic loci in diverse cell types. This system is an inexpensive, user-friendly delivery platform for non-viral genome reprogramming that we successfully applied in regulatory T cells (Tregs), γδ-T cells, B cells, NK cells, and primary and iPS-derived6 hematopoietic stem progenitor cells (HSPCs).
Folate deficiency facilitates coordination of KDM6A with p53 in response to DNA damage
Authors: Gao Jun , Zou Jizhen , Li Jianting , Zhang Yongfeng , Qiao Lina , Wang Fang , Bao Yihua , Hu Jin , Zhang Ting , Xie Qiu , Liu Changyun 
Published: March 2019

AbstractFolate contributes to the accumulation of DNA strand breaks (DSBs) in the genome. Kdm6a plays a critical role in early embryogenesis but it is unknown whether Kdm6a is involved in the DNA damage response under folate deficiency. Here, we established a low folate environment for mouse embryonic cells using a folate antagonist (methotrexate, MTX). We found increased enrichment of DSBs in Kdm6a in MTX-treated cells, resulting in reduced Kdm6a expression. MTX treatment enriched KDM6A in the nonhomologous end-joining (NHEJ) repair pathway and controlled the expression of the Ku heterodimer (Ku70/80) and XRCC4. The activation of NHEJ repair pathway-associated genes under folate deficiency relied on the specific interaction between KDM6A and p53. p53 silencing increased Ku heterodimer expression. In addition, in a neural tube defect (NTD) mouse model and low folate neural tube defect human brain samples, KDM6A levels were also decreased and accompanied by over-expression of Ku80. Our findings highlight how alterations in folate levels affect KDM6A with respect to DNA breakage and DNA repair, offering a new insight into the molecular function of KDM6A.Summary statementOur study demonstrates for the first time that in mammals, Kdm6a and p53 have synergistic effects during DNA fragmentation repair.
3D Packing Defects in Lipid Membrane as a Function of Membrane Order
Authors: Tripathy Madhusmita , Srivastava Anand 
Published: March 2019

AbstractLipid membrane packing defects are considered as essential parameter that regulates specific membrane binding of several peripheral proteins. In absence of direct experimental characterization, lipid packing defects and their role in the binding of peripheral proteins are generally investigated through computational studies, which have been immensely successful in unraveling the key steps of the membrane-binding process. However, packing defects are calculated using 2-dimensional projections and the crucial information on their depths is generally overlooked. Here we present a simple yet computationally efficient algorithm, which identifies these defects in 3-dimensions. We employ the algorithm to understand the nature of packing defects in flat bilayer membranes exhibiting liquid-ordered (Lo), liquid-disordered (Ld) and co-existing Lo/Ld phases. Our results indicate the presence of shallower and smaller defects in the Lo phase membranes as compared to the defects in Ld and mixed Lo/Ld phase membranes. Such analyses can elucidate the molecular scale mechanisms that drive the preferential localization of certain proteins to either of the liquid phases or their interface. Moreover, on the methodology front, our analyses suggest that the projection based 2-dimensional calculation of packing defects might result in inaccurate quantification of their sizes - a very important feature for membrane association of protein motifs, thus advocating the importance of the 3-dimensional calculations.
Feedback loops in the Plk4–STIL–HsSAS6 network coordinate site selection for procentriole formation
Authors: Takao Daisuke , Watanabe Koki , Kuroki Kanako , Kitagawa Daiju 
Published: March 2019

SUMMARYCentrioles are duplicated once in every cell cycle, ensuring the bipolarity of the mitotic spindle. Although the core components have been identified, how they cooperate to achieve high fidelity in centriole duplication remains poorly understood. Here, we show that in centriole duplication the accumulation of STIL and HsSAS6, components of the cartwheel structure, provides negative feedback in the centriolar dynamics of Plk4. By live-cell imaging of endogenously tagged proteins in human cells throughout the entire cell cycle, we quantitatively tracked the dynamics of the critical duplication factors: Plk4, STIL, and HsSAS6. Centriolar Plk4 peaks and then starts decreasing during the late G1 phase, which coincides with the accumulation of STIL at centrioles. Shortly thereafter, the HsSAS6 level increases steeply at the procentriole assembly site. We also show that both STIL and HsSAS6 are necessary for attenuating Plk4 levels. Furthermore, our mathematical modeling and simulation convincingly reproduce the dynamics of these three proteins at centrioles, and suggest that the STIL–HsSAS6 complex in the cartwheel has a negative feedback effect on centriolar Plk4. Combined, these findings illustrate how the dynamic behavior of and interactions between the critical duplication factors coordinate the centriole-duplication process.
Multiomics data analysis using tensor decomposition based unsupervised feature extraction --Comparison with DIABLO--
Authors: Taguchi Y-h. 
Published: March 2019

AbstractMultiomics data analysis is the central issue of genomics science. In spite of that, there are not well defined methods that can integrate multomics data sets, which are formatted as matrices with different sizes. In this paper, I propose the usage of tensor decomposition based unsupervised feature extraction as a data mining tool for multiomics data set. It can successfully integrate miRNA expression, mRNA expression and proteome, which were used as a demonstration example of DIABLO that is the recently proposed advanced method for the integrated analysis of multiomics data set.
Pharmacologically diverse antidepressant drugs disrupt the interaction of BDNF receptor TRKB and the endocytic adaptor AP-2
Authors: Fred Senem Merve , Laukkanen Liina , Brunello Cecilia A , Vesa Liisa , Goos Helka , Cardon Iseline , Moliner Rafael , Maritzen Tanja , Varjosalo Markku , Casarotto Plinio C , Castrén Eero 
Published: March 2019

AbstractAntidepressant drugs activate TRKB (tropomyosin-related kinase B), however it remains unclear whether these compounds employ a common mechanism for achieving this effect. We found by using mass spectrometry that the interaction of several proteins with TRKB was disrupted in the hippocampus of fluoxetine-treated animals (single intraperitoneal injection), including members of the AP-2 complex (adaptor protein complex-2) involved in vesicular endocytosis. The interaction of TRKB with the cargo-docking mu subunit of the AP-2 complex (AP2M) was disrupted by both acute and repeated fluoxetine treatment. However, while the coupling between full length TRKB and AP2M was disrupted by fluoxetine, the interaction between AP2M and the TRKB C-terminal peptide was resistant to this drug, indicating that the binding site targeted by fluoxetine must lie outside of the TRKB:AP2M interface. In addition to fluoxetine, other pharmacologically diverse antidepressants imipramine, rolipram, phenelzine, ketamine, and the ketamine metabolite 2R,6R-hydroxynorketamine (RR-HNK) also decreased the interaction between TRKB:AP2M in vitro, as measured by ELISA. Silencing the expression of AP2M in MG87.TRKB cell line led to increased surface positioning of TRKB and to a higher response to BDNF (brain-derived neurotrophic factor), observed as the levels of active TRKB. Moreover, animals haploinsufficient for the Ap2m1 gene displayed increased levels of active TRKB in vivo, as well as an enhanced cell surface expression of the receptor in cultured hippocampal neurons.Taken together, our data suggests that disruption of the TRKB:AP2M interaction is an effect shared by several antidepressants with diverse chemical structures and canonical modes of action.
Molecular basis of egg coat cross-linking sheds light on ZP1-associated female infertility
Authors: Nishimura Kaoru , Dioguardi Elisa , Nishio Shunsuke , Villa Alessandra , Han Ling , Matsuda Tsukasa , Jovine Luca 
Published: March 2019

AbstractInteraction between sperm and the egg zona pellucida (ZP) is the first step of mammalian fertilization, and ZP component ZP1 is important for fertility by covalently cross-linking ZP filaments into a matrix. Like ZP4, a structurally-related subunit absent in the mouse, ZP1 is predicted to contain an N-terminal ZP-N domain of unknown function. Characterization of ZP1 proteins carrying mutations from infertile patients suggests that, unlike in the mouse, filament cross-linking by ZP1 is crucial for human ZP assembly. We map the function of ZP1 to its ZP-N1 domain and determine crystal structures of ZP-N1 homodimers from a chicken homolog of ZP1. These reveal that ZP filament cross-linking is highly plastic and can be modulated by ZP1 fucosylation and, potentially, zinc sparks. Moreover, we show that ZP4 ZP-N1 forms non-covalent homodimers in chicken but not human. Together, these data identify human ZP1 cross-links as a promising target for non-hormonal contraception.
During hippocampal inactivation, grid cells maintain their synchrony, even when the grid pattern is lost
Authors: Almog Noam , Tocker Gilad , Bonnevie Tora , Moser Edvard , Moser May-Britt , Derdikman Dori 
Published: March 2019

AbstractThe grid cell network in the MEC has been subject to thorough testing and analysis, and many theories for their formation have been suggested. To test some of these theories we re-analyzed data from Bonnevie et al. (2013), in which the hippocampus was inactivated and grid cells were recorded in the MEC, to investigate whether the firing associations of grid cells depend on hippocampal inputs. Specifically, we examined temporal and spatial correlations in the firing times of simultaneously recorded grid cells before and during hippocampal inactivation. Our analysis revealed evidence of network coherence in grid cells even in the absence of hippocampal input to the MEC, both in regular grid cells and in those that became head-direction cells after hippocampal inactivation. This favors models which suggest that phase relations between grid cells in the MEC are dependent on intrinsic connectivity within the MEC.
Damage to the Right Insula Disrupts the Perception of Affective Touch
Authors: Kirsch Louise P. , Besharati Sahba , Papadaki Christina , Crucianelli Laura , Bertagnoli Sara , Ward Nick , Moro Valentina , Jenkinson Paul M. , Fotopoulou Aikaterini 
Published: March 2019

ABSTRACTSpecific, peripheral C-tactile afferents contribute to the perception of tactile pleasure, but the brain areas involved in their processing remain debated. We report the first human lesion study on the perception of C-tactile touch (N = 59), revealing that posterior and anterior right insula lesions reduce tactile, contralateral and ipsilateral pleasantness sensitivity, respectively. These findings are consistent with a posterior-to-anterior pattern of integration of interoceptive information in the frontoinsular junction.
Bacteriophage adherence to mucus mediates preventive protection against pathogenic bacteria
Authors: Almeida Gabriel MF , Laanto Elina , Ashrafi Roghaieh , Sundberg Lotta-Riina 
Published: March 2019

AbstractMetazoan mucosal surfaces are major interfaces between the organism and environment. These surfaces have been proposed to host bacteriophages in a symbiotic relationship with metazoans. Considering the so far poorly understood phage–mucus interaction and its role in ecological interactions and for mucosal bacterial infections, empirical evidence and model systems need to be established. Here, using the fish pathogenFlavobacterium columnareand rainbow trout (Oncorhynchus mykiss), we show that phages infecting the pathogen are capable of binding to primary mucus layers and protecting fish from infections. Furthermore, exposure to mucus changes the bacterial phenotype by increasing bacterial virulence and susceptibility to phage infections. Tests using other phage–bacterium pairs suggest that the relevance of mucus for bacteria and phages may be widespread in the biosphere. Therefore, interactions of bacteria and phages inside the mucus environment may be important for disease and evolution, and this phenomenon has significant potential to be exploited for preventive phage therapy approaches.
Contingent Convergence: The ability to detect convergent genomic evolution is dependent on population size and migration
Authors: Whiting James R. , Fraser Bonnie A. 
Published: March 2019

ABSTRACTOutlier scans, in which the genome is scanned for signatures of selection, have become a prominent tool in studies of local adaptation, and more recently studies of genetic convergence in natural populations. However, such methods have the potential to be confounded by features of demographic history, such as population size and migration, which are considerably varied across natural populations. In this study, we use forward-simulations to investigate and illustrate how several measures of genetic differentiation commonly used in outlier scans (FST, DXYand Δπ) are influenced by demographic variation across multiple sampling generations. In a factorial design with 16 treatments, we manipulate the presence/absence of founding bottlenecks (N of founding individuals), protracted bottlenecks (proportional size of diverging population) and migration rate between two populations with ancestral and derived phenotypic optima. Our results illustrate known constraints of individual measures associated with reduced population size and a lack of migration; but notably we demonstrate how relationships between measures are similarly dependent on demography. We find that false-positive signals of convergent evolution (the same simulated outliers detected in independent treatments) are attainable as a product of similar demographic treatment, and that outliers across different measures (particularly FSTand DXY) can occur with little influence of selection. Taken together, we show how underappreciated, yet quantifiable measures of demographic history can influence commonly employed methods for detecting selection.