bluuebunny/crossref_metadata_2025_split huggingface dataset:
Backstepping Based Automatically Controlled Angiogenic Inhibition Therapy
Authors: Doruk R. Ozgur 
Published: January 2020

AbstractIn this work, we present an automatically controlled angiogenic inhibition therapy where the variation profile of the inhibitory agent is generated by a control law that is derived using a back-stepping based control methodology. The angiogenic inhibition is described by a second order model representing the dynamics of tumor and supporting vasculature volumes. Backstepping control recursively stabilizes that dynamics and generates automatic control laws that allows the tumor volume to stay at a desired value. The desired value will be kept at one thousandth of its initial value. This will lead to a very small injection at the steady state. This is important as zero injection may lead to regrow of the tumor. The results will be presented in tabular and graphical forms. Tabular results present the variation of maximum injection rate and setup time. Graphical results present the variation of tumor and supporting vasculature volumes, injection rate and the tracking error between the reference and actual tumor volumes. In addition, we will also perform a simulation to test the capability of the closed loop to accomodate the parametric uncertainties in the rate constants. The uncertainties are represented by a random deviation in the range ±10% times the nominal value of the effected parameter. The control laws will be kept the same and the simulations will be repeated by 1000 times and each result will be superimposed on the graph. The area occupied by the curves will show the relative capability of the designs.
ntJoin: Fast and lightweight assembly-guided scaffolding using minimizer graphs
Authors: Coombe Lauren , Nikolić Vladimir , Chu Justin , Birol Inanc , Warren René L. 
Published: January 2020

AbstractSummaryThe ability to generate high-quality genome sequences is cornerstone to modern biological research. Even with recent advancements in sequencing technologies, many genome assemblies are still not achieving reference-grade. Here, we introduce ntJoin, a tool that leverages structural synteny between a draft assembly and reference sequence(s) to contiguate and correct the former with respect to the latter. Instead of alignments, ntJoin uses a lightweight mapping approach based on a graph data structure generated from ordered minimizer sketches. The tool can be used in a variety of different applications, including improving a draft assembly with a reference-grade genome, a short read assembly with a draft long read assembly, and a draft assembly with an assembly from a closely-related species. When scaffolding a human short read assembly using the reference human genome or a long read assembly, ntJoin improves the NGA50 length 23- and 13-fold, respectively, in under 13 m, using less than 11 GB of RAM. Compared to existing reference-guided assemblers, ntJoin generates highly contiguous assemblies faster and using less memory.Availability and implementationntJoin is written in C++ and Python, and is freely available athttps://github.com/bcgsc/ntjoin.Contactlcoombe@bcgsc.ca
RNA-Binding and Prion Domains: The Yin and Yang of Phase Separation
Authors: Gotor Nieves Lorenzo , Armaos Alexandros , Calloni Giulia , Vabulas R. Martin , de Groot Natalia Sanchez , Tartaglia Gian Gaetano 
Published: January 2020

AbstractBiomolecular condensates are membrane-less organelles mainly composed of proteins and RNAs that organize intracellular spaces and regulate biochemical reactions. The ability of proteins and RNAs to phase separate is encoded in their sequences, yet it is still unknown which domains drive the process and what are their specific roles. Here, we systematically investigated the human and yeast proteomes to find regions promoting biomolecular condensation. Using advanced computational models to predict the phase separation propensity of proteins, we designed a set of experiments to investigate the contributions of Prion-Like Domains (PrLDs) and RNA-Binding Domains (RBDs). We found that while just one PrLD is sufficient to drive protein condensation, multiple RBDs are needed to modulate the dynamicity of the assemblies. In the case of stress granule protein Pub1 we show that the PrLD promotes sequestration of protein partners and the RBD confers liquid-like behaviour to the condensate. Our work sheds light on the fine interplay between RBDs and PrLD to regulate formation of membrane-less organelles, opening up the avenue for their manipulation.
Drug mechanism-of-action discovery through the integration of pharmacological and CRISPR screens
Authors: Gonçalves Emanuel , Segura-Cabrera Aldo , Pacini Clare , Picco Gabriele , Behan Fiona M. , Jaaks Patricia , Coker Elizabeth A. , van der Meer Donny , Barthorpe Andrew , Lightfoot Howard ,   GDSC Screening Team, Leach Andrew R. , Lynch James T. , Sidders Ben , Crafter Claire , Iorio Francesco , Fawell Stephen , Garnett Mathew J. 
Published: January 2020

AbstractLow success rates during drug development are due in part to the difficulty of defining drug mechanism-of-action and molecular markers of therapeutic activity. Here, we integrated 199,219 drug sensitivity measurements for 397 unique anti-cancer drugs and genome-wide CRISPR loss-of-function screens in 484 cell lines to systematically investigatein cellulardrug mechanism-of-action. We observed an enrichment for positive associations between drug sensitivity and knockout of their nominal targets, and by leveraging protein-protein networks we identified pathways that mediate drug response. This revealed an unappreciated role of mitochondrial E3 ubiquitin-protein ligaseMARCH5in sensitivity to MCL1 inhibitors. We also estimated drug on-target and off-target activity, informing on specificity, potency and toxicity. Linking drug and gene dependency together with genomic datasets uncovered contexts in which molecular networks when perturbed mediate cancer cell loss-of-fitness, and thereby provide independent and orthogonal evidence of biomarkers for drug development. This study illustrates how integrating cell line drug sensitivity with CRISPR loss-of-function screens can elucidate mechanism-of-action to advance drug development.
A mitochondria-targeted antioxidant and a thyroid hormone affect carotenoid ketolase gene expression and bill redness in zebra finches
Authors: Cantarero Alejandro , Andrade Pedro , Carneiro Miguel , Moreno-Borrallo Adrián , Alonso-Alvarez Carlos 
Published: January 2020

ABSTRACTConspicuous ornaments in animals can evolve to reveal individual quality when their production/maintenance costs make them reliable as signals or if their expression level is intrinsically linked to quality by some unfalsifiable mechanism (quality indices). The latter has been mostly associated with traits constrained by body size. However, red ketocarotenoid-based coloured ornaments may also have evolved as quality indices because their production could be closely linked to individual metabolism and, particularly, to the cell respiration at the inner mitochondrial membrane (IMM). This mechanism would supposedly not depend on resource (yellow carotenoids) availability, thus discarding allocation trade-offs. A gene coding for a ketolase enzyme (CYP2J19) responsible for converting dietary yellow carotenoids to red ketocarotenoids has recently been described in birds. It is not known, however, if this ketolase is involved in mitochondrial metabolism and if its expression level and activity is resource independent. Here, we manipulated the metabolism of captive male zebra finches by an antioxidant designed to penetrate the IMM (mitoTEMPO) and a thyroid hormone (triiodothyronine; T3) with known hypermetabolic effects. The expression levels of a ketocarotenoid-based ornament (bill redness) andCYP2J19were measured. MitoTEMPO downregulatedCYP2J19expression, supporting the mitochondrial involvement in ketolase function. T3 also reducedCYP2J19expression, but at an intermediate dosage, this effect being buffered by mitoTEMPO. Bill redness seemed to show a similar interacting effect. Nevertheless, this faded whenCYP2J19expression level was controlled for as a covariate. We argue that the well-known mitoTEMPO effect in reducing mitochondrial reactive oxygen species (ROS) production (particularly superoxide) could have interfered on redox signalling mechanisms controlling ketolase transcription. High T3 levels, contrarily, can lead to high ROS production but also trigger compensatory mechanisms, which may explain the U-shaped effect with dosage onCYP2J19expression levels. BillCYP2J19expression values were also positively correlated to redness and circulating substrate carotenoid levels. Nonetheless, treatment effects did not change when controlling for blood carotenoid concentration, suggesting that resource-availability dependence was irrelevant. Finally, our findings reveal a role for thyroid hormones in the expression of carotenoid-based ornaments that has virtually been ignored until now.
Streptococcus pneumoniaeinfection promotes histone H3 dephosphorylation by modulating host PP1 phosphatase
Authors: Dong Wenyang , Rasid Orhan , Chevalier Christine , Connor Michael , Eldridge Matthew , Hamon Melanie Anne 
Published: January 2020

SummaryPathogenic bacteria can alter host gene expression through post-translational modifications of histones. We show for the first time that a natural colonizer,Streptococcus pneumoniae, also induces specific histone modifications, including robust dephosphorylation of histone H3 on serine 10, during infection of respiratory epithelial cells. Two bacterial factors are important for the induction of this modification: the bacterial toxin PLY, a pore-forming toxin, and the pyruvate oxidase SpxB, an enzyme responsible for H2O2production. The combined effects of PLY and H2O2lead to host signaling which culminates in H3S10 dephosphorylation, mediated by the host cell phosphatase PP1. Strikingly,S. pneumoniaeinfection induces dephosphorylation and associated activation of PP1 catalytic activity. Colonization of cells, which lacked active PP1, resulted in the impairment of intracellularS. pneumoniaesurvival. Interestingly, PP1 activation mediating H3S10 dephosphorylation is not restricted toS. pneumoniaeand appears to be a general epigenomic mechanism favoring intracellular survival.
CHLOROPLAST UNUSUAL POSITIONING 1 is a new type of actin nucleation factor in plants
Authors: Kong Sam-Geun , Shimada Atsushi , Kijima Saku T. , Hirose Keiko , Katoh Kaoru , Ahn Jeongsu , Higa Takeshi , Takano Akira , Nakamura Yuki , Suetsugu Noriyuki , Kohda Daisuke , Uyeda Taro Q. P. , Wada Masamitsu 
Published: January 2020

SUMMARYPlants have evolved unique responses to fluctuating light conditions in their environment. One such response, chloroplast photorelocation movement, optimizes photosynthesis under weak light and prevents photodamage under strong light. CHLOROPLAST UNUSUAL POSITIONING 1 (CHUP1) plays a pivotal role in the light-responsive chloroplast movements, which are driven by dynamic reorganization of chloroplast actin (cp-actin) filaments. In this study, we demonstrated that fluorescently tagged CHUP1 colocalized and was coordinately reorganized with cp-actin filaments during chloroplast movement inArabidopsis thaliana. The resulting asymmetric distribution of CHUP1 was reversibly regulated by the blue light receptor phototropin. X-ray crystallography indicated that the CHUP1 C-terminal domain shares structural similarity with the formin homology 2 (FH2) domain, although there is no sequence similarity between the two domains. The CHUP1 C-terminal domain stimulated actin polymerization in the presence of profilin. We conclude that CHUP1 is a novel, plant-specific actin nucleator that functions in cp-actin-based chloroplast movement.HighlightsBlue light changes the distribution pattern of CHUP1Formin FH2 and CHUP1 C-terminal domains are structurally similar but not homologousCHUP1 nucleates and severs actin filaments in vitroCHUP1 is a novel, plant-specific actin nucleator for chloroplast movement
Mg2+modulates the activity of hyperpolarization-activated calcium currents in plant cells
Authors: Lemtiri-Chlieh Fouad , Arold Stefan T. , Gehring Chris 
Published: January 2020

ABSTRACTHyperpolarization-activated calcium channels (HACCs) are found in the plasma membrane and tonoplast of many plant cell types where they have an important role in Ca2+-dependent signaling. The unusual gating properties of HACCs in plants, i.e., activation by membrane hyperpolarization rather than depolarization, dictates that HACCs are normally open at physiological hyperpolarized resting membrane potentials (the so called pump or P-state), thus, if not regulated, they would be continuously leaking Ca2+into cells. In guard cells, HACCs are permeable to Ca2+, Ba2+and Mg2+, activated by H2O2and the plant hormone abscisic acid (ABA) and their activity is greatly reduced by low amounts of free cytosolic Ca2+([Ca2+]Cyt) and hence will close during [Ca2+]Cytsurges. Here we demonstrate that the presence of the commonly used Mg-ATP inside the cell greatly reduces HACC activity especially at voltages ≤ −200 mV and that Mg2+causes this block. We therefore conclude, firstly, that physiological cytosolic Mg2+levels affect HACCs gating and that channel opening requires either high negative voltages (≥ −200 mV) and/or displacement of Mg2+away from the immediate vicinity of the channel. Secondly, based on structural comparisons with Mg2+-sensitive animal inward-rectifying K+channel, we propose that the likely candidate HACCS described here are cyclic nucleotide gated channels (CNGCs), many of which also contain a conserved di-acidic Mg2+-binding motif within their pores. This conclusion is consistent with the electrophysiological data. Finally, we propose that Mg2+, much like in animal cells, is an important component in Ca2+signalling and homeostasis in plants.
A Bayesian nonparametric semi-supervised model for integration of multiple single-cell experiments
Authors: Verma Archit , Engelhardt Barbara 
Published: January 2020

Joint analysis of multiple single cell RNA-sequencing (scRNA-seq) data is confounded by technical batch effects across experiments, biological or environmental variability across cells, and different capture processes across sequencing platforms. Manifold alignment is a principled, effective tool for integrating multiple data sets and controlling for confounding factors. We demonstrate that the semi-supervised t-distributed Gaussian process latent variable model (sstGPLVM), which projects the data onto a mixture of fixed and latent dimensions, can learn a unified low-dimensional embedding for multiple single cell experiments with minimal assumptions. We show the efficacy of the model as compared with state-of-the-art methods for single cell data integration on simulated data, pancreas cells from four sequencing technologies, induced pluripotent stem cells from male and female donors, and mouse brain cells from both spatial seqFISH+and traditional scRNA-seq.Code and data is available athttps://github.com/architverma1/sc-manifold-alignment
Mechanical Regulation of Microvascular Angiogenesis
Authors: Ruehle Marissa A. , Eastburn Emily A. , LaBelle Steven A. , Krishnan Laxminarayanan , Weiss Jeffrey A. , Boerckel Joel D. , Wood Levi B. , Guldberg Robert E. , Willett Nick J. 
Published: January 2020

AbstractNeovascularization is a critical early step toward successful tissue regeneration during wound healing. While vasculature has long been recognized as highly mechanosensitive (to fluid shear, pulsatile luminal pressure, etc.), the effects of extracellular matrix strains on angiogenesis are poorly understood. Previously, we found that dynamic matrix compressionin vivopotently regulated neovascular growth during tissue regeneration; however, whether matrix deformations directly regulate00 angiogenesis remained unknown. Here, we tested the effects of load initiation time, strain magnitude, and mode of compressive deformation (uniform compression vs. compressive indentation that also introduced shear stress) on neovascularization and key angiogenic and mechanotransduction signaling pathways by microvascular fragmentsin vitro. We hypothesized that neovascularization would be enhanced by delayed, moderate compression and inhibited by early, high magnitude compression and by compressive indentation. Consistent with our hypothesis, early, high magnitude loading inhibited vessel growth, while delayed loading enhanced vessel growth. Compressive indentation led to longer, more branched networks than uniform compression – particularly at high strain magnitude. Gene expression was differentially regulated by time of load initiation; genes associated with active angiogenic sprouts were downregulated by early loading but upregulated by delayed loading. Canonical gene targets of the YAP/TAZ mechanotransduction pathway were increased by loading and abrogated by pharmacological YAP inhibition. Together, these data demonstrate that neovascularization is directly responsive to dynamic matrix strain and is particularly sensitive to the timing of load initiation. This work further identifies putative mechanoregulatory angiogenic mechanisms and implicates a critical role for dynamic mechanical cues in vascularized tissue regeneration.Statement of SignificanceMechanical cues influence tissue regeneration, and although vasculature is known to be mechanically sensitive, remarkably little is known about the effects of bulk extracellular matrix deformation on the nascent vessel networks found in healing tissues. Here, we demonstrated that load initiation time, magnitude, and mode all regulate microvascular growth, as well as upstream angiogenic and mechanotransduction signaling pathways. Across all tested magnitudes and modes, microvascular network formation and upstream signaling were powerfully regulated by the timing of load initiation. This work provides a new foundational understanding of how extracellular matrix mechanics regulate angiogenesis and has critical implications for clinical translation of new regenerative medicine therapies and physical rehabilitation strategies designed to enhance revascularization during tissue regeneration.
Initial virome characterization of the common cnidarian lab modelNematostella vectensis
Authors: Lewandowska Magda , Hazan Yael , Moran Yehu 
Published: January 2020

AbstractThe role of viruses in forming a stable holobiont has been a subject of extensive research in the recent years. However, many emerging model organisms still lack any data on the composition of the associated viral communities. Here, we re-analyzed seven publicly available transcriptome datasets of the starlet sea anemoneNematostella vectensis, the most commonly used anthozoan lab model, and searched for viral sequences. We applied a straightforward, yet powerful approach ofde novoassembly followed by homology-based virus identification and a multi-step, thorough taxonomic validation. The comparison of different lab populations ofN. vectensisrevealed the existence of the core virome composed of 21 viral sequences, present in all adult datasets. Unexpectedly, we observed almost complete lack of viruses in the samples from the early developmental stages which together with the identification of the viruses shared with the major source of the food in the lab, the brine shrimpArtemia salina, shed new light on the course of viral species acquisition inN. vectensis. Our study provides an initial, yet comprehensive insight intoN. vectensisvirome and sets the first foundation for functional studies of viruses and antiviral systems in this lab model cnidarian.
A regulatory domain in the K2P2.1 (TREK-1) carboxyl-terminal allows for channel activation by monoterpenes
Authors: Arazi Eden , Blecher Galit , Zilberberg Noam 
Published: January 2020

AbstractPotassium K2P(‘leak’) channels conduct current across the entire physiological voltage range and carry leak or ‘background’ currents that are, in part, time- and voltage-independent. K2P2.1 channels (i.e., TREK-1, KCNK2) are highly expressed in excitable tissues, where they play a key role in the cellular mechanisms of neuroprotection, anesthesia, pain perception, and depression. Here, we report for the first time that human K2P2.1 channel activity is regulated by monoterpenes (MTs). We found that cyclic, aromatic monoterpenes containing a phenol moiety, such as carvacrol, thymol and 4-IPP had the most profound effect on current flowing through the channel (up to a 6-fold increase). By performing sequential truncation of the carboxyl-terminal domain of the channel and testing the activity of several channel regulators, we identified two distinct regulatory domains within this portion of the protein. One domain, as previously reported, was needed for regulation by arachidonic acid, anionic phospholipids and temperature changes. Within a second domain, a triple arginine residue motif (R344-346), an apparent PIP2-binding site, was found to be essential for regulation by holding potential changes and important for regulation by monoterpenes.
Architecture and self-assembly of theClostridium sporogenes/botulinumspore surface illustrate a general protective strategy across spore formers
Authors: Janganan Thamarai K. , Mullin Nic , Dafis-Sagarmendi Ainhoa , Brunt Jason , Tzokov Svetomir B. , Stringer Sandra , Moir Anne , Chaudhuri Roy , Fagan Robert P. , Hobbs Jamie K. , Bullough Per A. 
Published: January 2020

AbstractSpores, the infectious agents of many Firmicutes, are remarkably resilient cell forms. Even distant relatives have similar spore architectures incorporating protective proteinaceous envelopes. We reveal in nanometer detail how the outer envelope (exosporium) inClostridium sporogenes(surrogate forC. botulinumgroup I), and in other Clostridial relatives, forms a hexagonally symmetric molecular filter. A cysteine-rich protein, CsxA, when expressed inE. coli, self-assembles into a highly thermally stable structure identical to native exosporium. Like exosporium, CsxA arrays require harsh reducing conditions for disassembly. We conclude thatin vivo, CsxA self-organises into a highly resilient, disulphide cross-linked array decorated with additional protein appendages enveloping the forespore. This pattern is remarkably similar inBacillusspores, despite lack of protein homology. In both cases,intracellulardisulphide formation is favoured by the high lattice symmetry. We propose that cysteine-rich proteins identified in distantly related spore formers may adopt a similar strategy for intracellular assembly of robust protective structures.
PAX2 Induces Tubular-Like Structures in Normal and Ovarian Cancer Cells
Authors: Alwosaibai Kholoud , Al-Hujaily Ensaf Munawer , Alamri Salmah , Garson Kenneth , Vanderhyden Barbara C. 
Published: January 2020

AbstractIn adult tissues, PAX2 protein is expressed in normal oviductal epithelial cells but not in normal ovarian surface epithelial cells. Studies have reported that PAX2 is expressed in a subset of serous ovarian carcinoma cases but the role of PAX2 in the initiation and progression of ovarian cancer remains unknown. The aim of this study was to understand the biological consequences ofPax2expression in normal and cancerous mouse epithelial (MOSE) cells. We found thatPax2overexpression in both normal and cancerous ovarian epithelial cells induced the formation of vascular channels bothin vitroandin vivo. The results indicate a possible contribution of PAX2 to ovarian cancer progression by increasing the vascular channels to supply nutrients to the tumor cells.