bluuebunny/crossref_metadata_2025_split huggingface dataset:
The PI3K inhibitor copanlisib synergizes with sorafenib to induce cell death in hepatocellular carcinoma
Authors: Ye Liangtao , Mayerle Julia , Ziesch Andreas , Reiter Florian P. , Gerbes Alexander L. , De Toni Enrico N. 
Published: April 2019

AbstractSorafenib, a multikinase inhibitor targeting the Ras/Raf/MAPK (mitogen-activated protein kinase) and vascular endothelial growth factor signaling pathways is an established treatment option for patients with advanced-stage hepatocellular carcinoma (HCC); however, despite its clinical benefit, chemoresistance and disease progression eventually occur almost invariably during treatment. Activation of the PI3K/AKT (phosphatidylinositol-3-kinase/serine/threonine kinase) pathway plays a role in the pathogenesis of HCC and may contribute to determine resistance to sorafenib. We thus evaluated in vitro the effects of the combination of sorafenib and copanlisib, a PI3K inhibitor recently approved for clinical use. The effects of copanlisib alone and in combination with sorafenib were assessed in several HCC cell lines by proliferation and colony formation assays, fluorescence-activated cell sorting analyses, and western blot. In addition, sorafenib-resistant cell clones were used. Copanlisib strongly reduced cell viability and colony formation in different native and sorafenib-resistant HCC cell lines by affecting cyclin D1/CDK4/6 signaling and causing cell cycle arrest. Elevation of phosphorylated (p)-AKT was observed upon incubation with sorafenib and was consistently found in six different unstimulated sorafenib-resistant cell clones. Copanlisib counteracted sorafenib-induced phosphorylation of p-AKT and synergistically potentiated its antineoplastic effect. In summary, copanlisib shows potent anticancer activity as a single agent and acts synergistically in combination with sorafenib in human HCC. Combination of sorafenib with copanlisib represents a rational potential therapeutic option for advanced HCC.
Bridge ties bind collective memories
Authors: Momennejad Ida , Duker Ajua , Coman Alin 
Published: April 2019

AbstractFrom families to nations, what binds individuals in social groups is, to a large degree, their shared beliefs, norms, and memories. These emergent outcomes are thought to occur because communication among individuals results in community-wide synchronization. Here, we use experimental manipulations in lab-created networks to investigate how the temporal dynamics of conversations shape the formation of collective memories. We show that when individuals that bridge between clusters (i.e., bridge ties) communicate early on in a series of networked interactions, the network reaches higher mnemonic convergence compared to when individuals first interact within clusters (i.e., cluster ties). This effect, we show, is due to the tradeoffs between initial information diversity and accumulated overlap over time. Our approach provides a framework to analyze and design interventions in social networks that optimize information sharing and diminish the likelihood of information bubbles and polarization.
Strong neuron-to-body coupling implies weak neuron-to-neuron coupling in motor cortex
Authors: Kells Patrick A. , Gautam Shree Hari , Fakhraei Leila , Li Jingwen , Shew Woodrow L. 
Published: April 2019

AbstractCortical neurons can be strongly or weakly coupled to the network in which they are embedded, firing in sync with the majority or firing independently. Both these scenarios have potential computational advantages in motor cortex. Commands to the body might be more robustly conveyed by a strongly coupled population, whereas a motor code with greater information capacity could be implemented by neurons that fire more independently. Which of these scenarios prevails? Here we measure neuron-to-body coupling and neuron-to-population coupling for neurons in motor cortex of freely moving rats. We find that neurons with high and low population coupling coexist, and that population coupling was tunable by manipulating inhibitory signaling. Importantly, neurons with different population coupling tend to serve different functional roles. Those with strong population coupling are not involved with body movement. In contrast, neurons with high neuron-to-body coupling are weakly coupled to other neurons in the cortical population.
On the computational complexity of curing non-stoquastic Hamiltonians
Authors: Marvian Milad , Lidar Daniel A. , Hen Itay 
Published: April 2019

AbstractQuantum many-body systems whose Hamiltonians are non-stoquastic, i.e., have positive off-diagonal matrix elements in a given basis, are known to pose severe limitations on the efficiency of Quantum Monte Carlo algorithms designed to simulate them, due to the infamous sign problem. We study the computational complexity associated with ‘curing’ non-stoquastic Hamiltonians, i.e., transforming them into sign-problem-free ones. We prove that if such transformations are limited to single-qubit Clifford group elements or general single-qubit orthogonal matrices, finding the curing transformation is NP-complete. We discuss the implications of this result.
A revised biosynthetic pathway for the cofactor F420 in prokaryotes
Authors: Bashiri Ghader , Antoney James , Jirgis Ehab N. M. , Shah Mihir V. , Ney Blair , Copp Janine , Stuteley Stephanie M. , Sreebhavan Sreevalsan , Palmer Brian , Middleditch Martin , Tokuriki Nobuhiko , Greening Chris , Scott Colin , Baker Edward N. , Jackson Colin J. 
Published: April 2019

AbstractCofactor F420 plays critical roles in primary and secondary metabolism in a range of bacteria and archaea as a low-potential hydride transfer agent. It mediates a variety of important redox transformations involved in bacterial persistence, antibiotic biosynthesis, pro-drug activation and methanogenesis. However, the biosynthetic pathway for F420 has not been fully elucidated: neither the enzyme that generates the putative intermediate 2-phospho-l-lactate, nor the function of the FMN-binding C-terminal domain of the γ-glutamyl ligase (FbiB) in bacteria are known. Here we present the structure of the guanylyltransferase FbiD and show that, along with its archaeal homolog CofC, it accepts phosphoenolpyruvate, rather than 2-phospho-l-lactate, as the substrate, leading to the formation of the previously uncharacterized intermediate dehydro-F420-0. The C-terminal domain of FbiB then utilizes FMNH2 to reduce dehydro-F420-0, which produces mature F420 species when combined with the γ-glutamyl ligase activity of the N-terminal domain. These new insights have allowed the heterologous production of F420 from a recombinant F420 biosynthetic pathway in Escherichia coli.
Root traits and belowground herbivores relate to plant–soil feedback variation among congeners
Authors: Wilschut Rutger A. , van der Putten Wim H. , Garbeva Paolina , Harkes Paula , Konings Wouter , Kulkarni Purva , Martens Henk , Geisen Stefan 
Published: April 2019

AbstractPlant–soil feedbacks contribute to vegetation dynamics by species-specific interactions between plants and soil biota. Variation in plant–soil feedbacks can be predicted by root traits, successional position, and plant nativeness. However, it is unknown whether closely related plant species develop more similar plant–soil feedbacks than more distantly related species. Where previous comparisons included plant species from distant phylogenetic positions, we studied plant–soil feedbacks of congeneric species. Using eight intra-continentally range-expanding and nativeGeraniumspecies, we tested relations between phylogenetic distances, chemical and structural root traits, root microbiomes, and plant–soil feedbacks. We show that root chemistry and specific root length better predict bacterial and fungal community composition than phylogenetic distance. Negative plant–soil feedback strength correlates with root-feeding nematode numbers, whereas microbiome dissimilarity, nativeness, or phylogeny does not predict plant–soil feedbacks. We conclude that root microbiome variation among congeners is best explained by root traits, and that root-feeding nematode abundances predict plant–soil feedbacks.
Pellino1 regulates reversible ATM activation via NBS1 ubiquitination at DNA double-strand breaks
Authors: Ha Geun-Hyoung , Ji Jae-Hoon , Chae Sunyoung , Park Jihyun , Kim Suhyeon , Lee Jin-Kwan , Kim Yonghyeon , Min Sunwoo , Park Jeong-Min , Kang Tae-Hong , Lee Ho , Cho Hyeseong , Lee Chang-Woo 
Published: April 2019

AbstractDNA double-strand break (DSB) signaling and repair are critical for genome integrity. They rely on highly coordinated processes including posttranslational modifications of proteins. Here we show that Pellino1 (Peli1) is a DSB-responsive ubiquitin ligase required for the accumulation of DNA damage response proteins and efficient homologous recombination (HR) repair. Peli1 is activated by ATM-mediated phosphorylation. It is recruited to DSB sites in ATM- and γH2AX-dependent manners. Interaction of Peli1 with phosphorylated histone H2AX enables it to bind to and mediate the formation of K63-linked ubiquitination of NBS1, which subsequently results in feedback activation of ATM and promotes HR repair. Collectively, these results provide a DSB-responsive factor underlying the connection between ATM kinase and DSB-induced ubiquitination.
NDRG4 promoter hypermethylation is a mechanistic biomarker associated with metastatic progression in breast cancer patients
Authors: Jandrey Elisa H. F. , Moura Ricardo P. , Andrade Luciana N. S. , Machado Camila L. , Campesato Luiz Felipe , Leite Katia Ramos M. , Inoue Lilian T. , Asprino Paula F. , da Silva Ana Paula M. , de Barros Alfredo Carlos S. D. , Carvalho Andre , de Lima Vladmir C. , Carraro Dirce M. , Brentani Helena P. , da Cunha Isabela W. , Soares Fernando A. , Parmigiani Raphael B. , Chammas Roger , Camargo Anamaria A. , Costa Érico T. 
Published: April 2019

AbstractThe risk of developing metastatic disease in breast cancer patients is traditionally predictable based on the number of positive axillary lymph nodes, complemented with additional clinicopathological factors. However, since lymph node-negative patients have a 20–30% probability of developing metastatic disease, lymph node information alone is insufficient to accurately assess individual risk. Molecular approaches, such as multigene expression panels, analyze a set of cancer-related genes that more accurately predict the early risk of metastasis and the treatment response. Here, we present N-Myc downstream-regulated gene 4 (NDRG4) epigenetic silencing as a mechanistic biomarker of metastasis in ductal invasive breast tumors. While aberrant NDRG4 DNA hypermethylation is significantly associated with the development of metastatic disease, downregulation of NDRG4 transcription and protein expression is functionally associated with enhanced lymph node adhesion and cell mobility. Here, we show that epigenetic silencing of NDRG4 modulates integrin signaling by assembling β1-integrins into large punctate clusters at the leading edge of tumor cells to promote an “adhesive switch,” decreasing cell adhesion to fibronectin and increasing cell adhesion and migration towards vitronectin, an important component of human lymph nodes. Taken together, our functional and clinical observations suggest that NDRG4 is a potential mechanistic biomarker in breast cancer that is functionally associated with metastatic disease.
Heavy ion ranges from first-principles electron dynamics
Authors: Sand Andrea E. , Ullah Rafi , Correa Alfredo A. 
Published: April 2019

AbstractThe effects of incident energetic particles, and the modification of materials under irradiation, are governed by the mechanisms of energy losses of ions in matter. The complex processes affecting projectiles spanning many orders of magnitude in energy depend on both ion and electron interactions. Developing multi-scale modeling methods that correctly capture the relevant processes is crucial for predicting radiation effects in diverse conditions. In this work, we obtain channeling ion ranges for tungsten, a prototypical heavy ion, by explicitly simulating ion trajectories with a method that takes into account both the nuclear and the electronic stopping power. The electronic stopping power of self-ion irradiated tungsten is obtained from first-principles time-dependent density functional theory (TDDFT). Although the TDDFT calculations predict a lower stopping power than SRIM by a factor of three, our result shows very good agreement in a direct comparison with ion range experiments. These results demonstrate the validity of the TDDFT method for determining electronic energy losses of heavy projectiles, and in turn its viability for the study of radiation damage.
Modeling Parkinson’s disease in midbrain-like organoids
Authors: Smits Lisa M. , Reinhardt Lydia , Reinhardt Peter , Glatza Michael , Monzel Anna S. , Stanslowsky Nancy , Rosato-Siri Marcelo D. , Zanon Alessandra , Antony Paul M. , Bellmann Jessica , Nicklas Sarah M. , Hemmer Kathrin , Qing Xiaobing , Berger Emanuel , Kalmbach Norman , Ehrlich Marc , Bolognin Silvia , Hicks Andrew A. , Wegner Florian , Sterneckert Jared L. , Schwamborn Jens C. 
Published: April 2019

AbstractModeling Parkinson’s disease (PD) using advanced experimental in vitro models is a powerful tool to study disease mechanisms and to elucidate unexplored aspects of this neurodegenerative disorder. Here, we demonstrate that three-dimensional (3D) differentiation of expandable midbrain floor plate neural progenitor cells (mfNPCs) leads to organoids that resemble key features of the human midbrain. These organoids are composed of midbrain dopaminergic neurons (mDANs), which produce and secrete dopamine. Midbrain-specific organoids derived from PD patients carrying the LRRK2-G2019S mutation recapitulate disease-relevant phenotypes. Automated high-content image analysis shows a decrease in the number and complexity of mDANs in LRRK2-G2019S compared to control organoids. The floor plate marker FOXA2, required for mDAN generation, increases in PD patient-derived midbrain organoids, suggesting a neurodevelopmental defect in mDANs expressing LRRK2-G2019S. Thus, we provide a robust method to reproducibly generate 3D human midbrain organoids containing mDANs to investigate PD-relevant patho-mechanisms.
All semiconductor enhanced high-harmonic generation from a single nanostructured cone
Authors: Franz Dominik , Kaassamani Shatha , Gauthier David , Nicolas Rana , Kholodtsova Maria , Douillard Ludovic , Gomes Jean-Thomas , Lavoute Laure , Gaponov Dmitry , Ducros Nicolas , Février Sebastien , Biegert Jens , Shi Liping , Kovacev Milutin , Boutu Willem , Merdji Hamed 
Published: April 2019

AbstractThe enhancement and control of non-linear phenomena at a nanometer scale has a wide range of applications in science and in industry. Among these phenomena, high-harmonic generation in solids is a recent focus of research to realize next generation petahertz optoelectronic devices or compact all solid state EUV sources. Here, we report on the realization of the first nanoscale high harmonic source. The strong field regime is reached by confining the electric field from a few nanojoules femtosecond laser in a single 3D semiconductor waveguide. We reveal a strong competition between enhancement of coherent harmonics and incoherent fluorescence favored by excitonic processes. However, far from the band edge, clear enhancement of the harmonic emission is reported with a robust sustainability offering a compact nanosource for applications. We illustrate the potential of our harmonic nano-device by performing a coherent diffractive imaging experiment. Ultra-compact UV/X-ray nanoprobes are foreseen to have other applications such as petahertz electronics, nano-tomography or nano-medicine.
Neural correlates of abnormal auditory feedback processing during speech production in Alzheimer’s disease
Authors: Ranasinghe Kamalini G. , Kothare Hardik , Kort Naomi , Hinkley Leighton B. , Beagle Alexander J. , Mizuiri Danielle , Honma Susanne M. , Lee Richard , Miller Bruce L. , Gorno-Tempini Maria Luisa , Vossel Keith A. , Houde John F. , Nagarajan Srikantan S. 
Published: April 2019

AbstractAccurate integration of sensory inputs and motor commands is essential to achieve successful behavioral goals. A robust model of sensorimotor integration is the pitch perturbation response, in which speakers respond rapidly to shifts of the pitch in their auditory feedback. In a previous study, we demonstrated abnormal sensorimotor integration in patients with Alzheimer’s disease (AD) with an abnormally enhanced behavioral response to pitch perturbation. Here we examine the neural correlates of the abnormal pitch perturbation response in AD patients, using magnetoencephalographic imaging. The participants phonated the vowel /α/ while a real-time signal processor briefly perturbed the pitch (100 cents, 400 ms) of their auditory feedback. We examined the high-gamma band (65–150 Hz) responses during this task. AD patients showed significantly reduced left prefrontal activity during the early phase of perturbation and increased right middle temporal activity during the later phase of perturbation, compared to controls. Activity in these brain regions significantly correlated with the behavioral response. These results demonstrate that impaired prefrontal modulation of speech-motor-control network and additional recruitment of right temporal regions are significant mediators of aberrant sensorimotor integration in patients with AD. The abnormal neural integration mechanisms signify the contribution of cortical network dysfunction to cognitive and behavioral deficits in AD.
Fault Dynamics of the 1999 Chi-Chi earthquake: clues from nanometric geochemical analysis of fault gouges
Authors: Li Wen-Hsien , Lee Chi-Hung , Ma Ma-Hsuan , Huang Ping Jung , Wu Sheng Yun 
Published: April 2019

AbstractThe 1999 Chi-Chi, Taiwan earthquake (Mw 7.6) produced surface ruptures for about 90 km along the north-south trending Chelungpu fault, with surface displacements of up to 12 m. Based on the combination of nanoscopic investigation and geochemistry analysis of core samples from a 450 m long inclined borehole drilled through the slip zone, we suggest the dynamical processes that likely occurred in the northern portion of the Chelungpu fault during the faulting. Our analysis revealed that the frictional heating could have reached 1200 °C, which would cause most of the siderite in the fault gouge to evaporate, resulting in a large amount of nano-size siderite grains with a mean diameter 20 nm. These nano grains could have acted as a mechanical lubricant to reduce the dynamic frictional resistance during sliding, giving rise to the large but smooth type of slipping seen in the north.
Generating retinal flow maps from structural optical coherence tomography with artificial intelligence
Authors: Lee Cecilia S. , Tyring Ariel J. , Wu Yue , Xiao Sa , Rokem Ariel S. , DeRuyter Nicolaas P. , Zhang Qinqin , Tufail Adnan , Wang Ruikang K. , Lee Aaron Y. 
Published: April 2019

AbstractDespite advances in artificial intelligence (AI), its application in medical imaging has been burdened and limited by expert-generated labels. We used images from optical coherence tomography angiography (OCTA), a relatively new imaging modality that measures retinal blood flow, to train an AI algorithm to generate flow maps from standard optical coherence tomography (OCT) images, exceeding the ability and bypassing the need for expert labeling. Deep learning was able to infer flow from single structural OCT images with similar fidelity to OCTA and significantly better than expert clinicians (P < 0.00001). Our model allows generating flow maps from large volumes of previously collected OCT data in existing clinical trials and clinical practice. This finding demonstrates a novel application of AI to medical imaging, whereby subtle regularities between different modalities are used to image the same body part and AI is used to generate detailed inferences of tissue function from structure imaging.
Bubble cascade in Guinness beer is caused by gravity current instability
Authors: Watamura Tomoaki , Iwatsubo Fumiya , Sugiyama Kazuyasu , Yamamoto Kenichiro , Yotsumoto Yuko , Shiono Takashi 
Published: April 2019

AbstractThe downward movement of the bubble-texture in a glass of Guinness beer is a fascinating fluid flow driven by the buoyant force of a large number of small-diameter bubbles. This texture motion is a frequently observed phenomenon on pub tables. The physical mechanism of the texture-formation has been discussed previously, but inconsistencies exist between these studies. We performed experiments on the bubble distribution in Guinness poured in an inclined container, and observed how the texture forms. We also report the texture-formation in controllable experiments using particle suspensions with precisely specified diameters and volume-concentrations. Our specific measurement methods based on laser-induced-fluorescence provide details of the spatio-temporal profile of the liquid phase velocity. The hydrodynamic condition for the texture-formation is analogous to the critical point of the roll-wave instability in a fluid film, which can be commonly observed in water films sliding downhill on a rainy day. Here, we identify the critical condition for the texture-formation and conclude that the roll-wave instability of the gravity current is responsible for the texture-formation in a glass of Guinness beer.
Measuring Liquid Drop Properties on Nanoscale 1D Patterned Photoresist Structures
Authors: Faria-Briceno Juan J. , Neumann Alexander , Schunk P. Randall , Brueck S. R. J. 
Published: April 2019

AbstractThis communication reports liquid wetting properties of DI-water on one-dimensional nano-patterned photoresist lines atop a silicon substrate as the pattern period is varied from 0.3- to 1.0-µm. Both constant photoresist height and constant width/height ratios are investigated. The line/period ratio was fixed at 0.3 (0.4) for different measurement sequences. The surface of the photoresist was treated with a short CHF3 reactive ion etch to ensure consistent hydrophobic photoresist: water surface energies. Average parallel contact angle (θ||), average perpendicular contact angle (θ⊥), drop width (W), and drop length (L) at constant volume were measured on nano-patterned surfaces fabricated with interferometric lithography. Both θ|| and θ⊥ contact angles increase as the period (0.3- to 1-μm) increases; the θ|| spreading rate is faster than θ⊥ due to pinning on the grooves resulting in an elongated drop shape. The traditional Wenzel and Cassie-Baxter models of drop contact angles were developed for isotropic random 2D roughness and do not account for the anisotropy induced by the 1D line patterns. The observed angular variations with period are not consistent with either model. Understanding liquid wetting properties and hydrophobicity on 1D silicon surfaces has many applications in lab-on-a-chip, micro/nano-fluidic devices, roll-to-roll nano-imprint fabrication, self-cleaning surfaces, and micro-reactors.