bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resveratrol chemosensitizes HER-2-overexpressing breast cancer cells to docetaxel chemoresistance by inhibiting docetaxel-mediated activation of HER-2–Akt axis
Authors: Vinod B S , Nair H H , Vijayakurup V , Shabna A , Shah S , Krishna A , Pillai K S , Thankachan S , Anto R J 
Published: December 2015

AbstractAs breast cancer cells often develop chemoresistance, better therapeutic options are in search to circumvent it. Here we demonstrate that human epidermal growth factor receptor-2 (HER-2)-overexpressing breast cancer cells resist docetaxel-induced cytotoxicity by upregulating HER-2 and its activity downstream, through Akt and mitogen-activated protein kinase (MAPK) pathways. We observed that introducing resveratrol as a chemosensitizer in docetaxel chemotherapy blocks upregulation and activation of HER-2 in addition to blocking downstream signaling pathways such as Akt. Resveratrol and docetaxel combination results in the synergistic induction of cell death in HER-2-overexpressing SK-BR-3 cells, whereas introduction of wild-type HER-2 in MDA-MD-231 cells increased the resistance to docetaxel. Dominant-negative HER-2 sensitizes SK-BR-3 cells to docetaxel. Our study identified a new synergistic therapeutic combination that targets HER-2-induced breast cancer resistance and might help to overcome therapeutic resistance during breast cancer therapy. The synergism of docetaxel and resveratrol was maximum in SK-BR-3, which is unique among the cell lines studied, due to its high expression status of HER-2, a receptor known to dictate the signaling environment of breast cancer cells. Docetaxel could further induce HER-2 activity in these cells, which was downregulated on resveratrol treatment. Transfection of DN-HER-2 in SK-BR-3 cells inhibits the synergism as the transfection itself sensitizes these cells to docetaxel, leaving no role for resveratrol, whereas ectopic expression of HER-2 introduces the synergism in MDA-MB-231, the triple-negative cell line, in which the synergism was minimum, attesting the crucial role of HER-2 in suppressing the sensitivity to docetaxel. Single-agent docetaxel induced HER-2-mediated resistance to cell death, which was blocked by resveratrol. Resveratrol also downregulated docetaxel-induced activation of MAPK and Akt, survival signaling pathways downstream of HER-2. In short, this study, for the first time, establishes the role of HER-2–Akt signaling axis in regulating the synergistic effect of docetaxel and resveratrol in breast cancer cells overexpressing HER-2.
Resonant magnetoelastic microstructures for wireless actuation of liquid flow on 3D surfaces and use in glaucoma drainage implants
Authors: Pepakayala Venkatram , Stein Joshua , Gianchandani Yogesh 
Published: December 2015

AbstractMagnetoelastic resonators made from metal alloy foils are widely used for miniature wireless anti-theft tags and have also been explored for use in various sensing applications. Through annealing within three-dimensional (3D) molds, these foils can be formed into curved structures. Consequently, magnetoelastic materials present an opportunity for the development of a new class of wireless, actuators that have small form factors and low surface profiles and that can conform to curved surfaces. This paper describes passive, wireless, resonant magnetoelastic actuators intended for the generation of fluid flow on the surfaces of implantable Ahmed glaucoma drainage devices. The actuators are remotely excited to resonance using a magnetic field generated by external coils. The fluid flow is intended to limit cellular adhesion to the surface of the implant, as this adhesion can ultimately lead to implant encapsulation and failure. The actuators are micromachined from planar 29-μm-thick foils of Metglas 2826MB (Fe40Ni38Mo4B18), an amorphous magnetoelastic alloy, using photochemical machining. Measuring 10.3 × 5.6 mm2, the planar structures are annealed in 3D molds to conform to the surface of the drainage device, which has an aspherical curvature. Six actuator designs are described, with varying shapes and resonant mode shapes. The resonant frequencies for the different designs vary from 520 Hz to 4.7 kHz. Flow velocities of up to 266 μm s−1 are recorded at a wireless activation range of 25–30 mm, with peak actuator vibration amplitudes of 1.5 μm. Integrated actuators such as those described here have the potential to greatly enhance the effectiveness of glaucoma drainage devices at lowering eye pressure and may also be useful in other areas of medicine.
Ultrahigh-throughput discovery of promiscuous enzymes by picodroplet functional metagenomics
Authors: Colin Pierre-Yves , Kintses Balint , Gielen Fabrice , Miton Charlotte M. , Fischer Gerhard , Mohamed Mark F. , Hyvönen Marko , Morgavi Diego P. , Janssen Dick B , Hollfelder Florian 
Published: December 2015

AbstractUnculturable bacterial communities provide a rich source of biocatalysts, but their experimental discovery by functional metagenomics is difficult, because the odds are stacked against the experimentor. Here we demonstrate functional screening of a million-membered metagenomic library in microfluidic picolitre droplet compartments. Using bait substrates, new hydrolases for sulfate monoesters and phosphotriesters were identified, mostly based on promiscuous activities presumed not to be under selection pressure. Spanning three protein superfamilies, these break new ground in sequence space: promiscuity now connects enzymes with only distantly related sequences. Most hits could not have been predicted by sequence analysis, because the desired activities have never been ascribed to similar sequences, showing how this approach complements bioinformatic harvesting of metagenomic sequencing data. Functional screening of a library of unprecedented size with excellent assay sensitivity has been instrumental in identifying rare genes constituting catalytically versatile hubs in sequence space as potential starting points for the acquisition of new functions.
Recruitment of Pontin/Reptin by E2f1 amplifies E2f transcriptional response during cancer progression
Authors: Tarangelo Amy , Lo Nathanael , Teng Rebecca , Kim Eunsun , Le Linh , Watson Deborah , Furth Emma E. , Raman Pichai , Ehmer Ursula , Viatour Patrick 
Published: December 2015

AbstractChanges in gene expression during tumorigenesis are often considered the consequence of de novo mutations occurring in the tumour. An alternative possibility is that the transcriptional response of oncogenic transcription factors evolves during tumorigenesis. Here we show that aberrant E2f activity, following inactivation of the Rb gene family in a mouse model of liver cancer, initially activates a robust gene expression programme associated with the cell cycle. Slowly accumulating E2f1 progressively recruits a Pontin/Reptin complex to open the chromatin conformation at E2f target genes and amplifies the E2f transcriptional response. This mechanism enhances the E2f-mediated transactivation of cell cycle genes and initiates the activation of low binding affinity E2f target genes that regulate non-cell-cycle functions, such as the Warburg effect. These data indicate that both the physiological and the oncogenic activities of E2f result in distinct transcriptional responses, which could be exploited to target E2f oncogenic activity for therapy.
Quadratic Fermi node in a 3D strongly correlated semimetal
Authors: Kondo Takeshi , Nakayama M. , Chen R. , Ishikawa J. J. , Moon E.-G. , Yamamoto T. , Ota Y. , Malaeb W. , Kanai H. , Nakashima Y. , Ishida Y. , Yoshida R. , Yamamoto H. , Matsunami M. , Kimura S. , Inami N. , Ono K. , Kumigashira H. , Nakatsuji S. , Balents L. , Shin S. 
Published: December 2015

AbstractStrong spin–orbit coupling fosters exotic electronic states such as topological insulators and superconductors, but the combination of strong spin–orbit and strong electron–electron interactions is just beginning to be understood. Central to this emerging area are the 5d transition metal iridium oxides. Here, in the pyrochlore iridate Pr2Ir2O7, we identify a non-trivial state with a single-point Fermi node protected by cubic and time-reversal symmetries, using a combination of angle-resolved photoemission spectroscopy and first-principles calculations. Owing to its quadratic dispersion, the unique coincidence of four degenerate states at the Fermi energy, and strong Coulomb interactions, non-Fermi liquid behaviour is predicted, for which we observe some evidence. Our discovery implies that Pr2Ir2O7 is a parent state that can be manipulated to produce other strongly correlated topological phases, such as topological Mott insulator, Weyl semimetal, and quantum spin and anomalous Hall states.
Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin
Authors: Chan Pan F. , Srikannathasan Velupillai , Huang Jianzhong , Cui Haifeng , Fosberry Andrew P. , Gu Minghua , Hann Michael M. , Hibbs Martin , Homes Paul , Ingraham Karen , Pizzollo Jason , Shen Carol , Shillings Anthony J. , Spitzfaden Claus E. , Tanner Robert , Theobald Andrew J. , Stavenger Robert A. , Bax Benjamin D. , Gwynn Michael N. 
Published: December 2015

AbstractNew antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand DNA breaks. Here we report the first co-crystal structures of the antibacterial QPT-1 and the anticancer drug etoposide with Staphylococcus aureus DNA gyrase, showing binding at the same sites in the cleaved DNA as the fluoroquinolone moxifloxacin. Unlike moxifloxacin, QPT-1 and etoposide interact with conserved GyrB TOPRIM residues rationalizing why QPT-1 can overcome fluoroquinolone resistance. Our data show etoposide’s antibacterial activity is due to DNA gyrase inhibition and suggests other anticancer agents act similarly. Analysis of multiple DNA gyrase co-crystal structures, including asymmetric cleavage complexes, led to a ‘pair of swing-doors’ hypothesis in which the movement of one DNA segment regulates cleavage and religation of the second DNA duplex. This mechanism can explain QPT-1’s bacterial specificity. Structure-based strategies for developing topo2A antibacterials are suggested.
Corticostriatal pathways contribute to the natural time course of positive mood
Authors: Admon Roee , Pizzagalli Diego A. 
Published: December 2015

AbstractThe natural time course of mood includes both acute responses to stimuli and spontaneous fluctuations. To date, neuroimaging studies have focused on either acute affective responses or spontaneous neural fluctuations at rest but no prior study has concurrently probed both components, or how mood disorders might modulate these processes. Here, using fMRI, we capture the acute affective and neural responses to naturalistic positive mood induction, as well as their spontaneous fluctuations during resting states. In both healthy controls and individuals with a history of depression, our manipulation acutely elevates positive mood and ventral striatum activation. Only controls, however, sustain positive mood over time, and this effect is accompanied by the emergence of a reciprocal relationship between the ventral striatum and medial prefrontal cortex during ensuing rest. Findings suggest that corticostriatal pathways contribute to the natural time course of positive mood fluctuations, while disturbances of those neural interactions may characterize mood disorder.
Hybrid integrated biological–solid-state system powered with adenosine triphosphate
Authors: Roseman Jared M. , Lin Jianxun , Ramakrishnan Siddharth , Rosenstein Jacob K. , Shepard Kenneth L. 
Published: December 2015

AbstractThere is enormous potential in combining the capabilities of the biological and the solid state to create hybrid engineered systems. While there have been recent efforts to harness power from naturally occurring potentials in living systems in plants and animals to power complementary metal-oxide-semiconductor integrated circuits, here we report the first successful effort to isolate the energetics of an electrogenic ion pump in an engineered in vitro environment to power such an artificial system. An integrated circuit is powered by adenosine triphosphate through the action of Na+/K+ adenosine triphosphatases in an integrated in vitro lipid bilayer membrane. The ion pumps (active in the membrane at numbers exceeding 2 × 106 mm−2) are able to sustain a short-circuit current of 32.6 pA mm−2 and an open-circuit voltage of 78 mV, providing for a maximum power transfer of 1.27 pW mm−2 from a single bilayer. Two series-stacked bilayers provide a voltage sufficient to operate an integrated circuit with a conversion efficiency of chemical to electrical energy of 14.9%.
Tank binding kinase 1 is a centrosome-associated kinase necessary for microtubule dynamics and mitosis
Authors: Pillai Smitha , Nguyen Jonathan , Johnson Joseph , Haura Eric , Coppola Domenico , Chellappan Srikumar 
Published: December 2015

AbstractTANK Binding Kinase 1 (TBK1) is a non-canonical IκB kinase that contributes to KRAS-driven lung cancer. Here we report that TBK1 plays essential roles in mammalian cell division. Specifically, levels of active phospho-TBK1 increase during mitosis and localize to centrosomes, mitotic spindles and midbody, and selective inhibition or silencing of TBK1 triggers defects in spindle assembly and prevents mitotic progression. TBK1 binds to the centrosomal protein CEP170 and to the mitotic apparatus protein NuMA, and both CEP170 and NuMA are TBK1 substrates. Further, TBK1 is necessary for CEP170 centrosomal localization and binding to the microtubule depolymerase Kif2b, and for NuMA binding to dynein. Finally, selective disruption of the TBK1–CEP170 complex augments microtubule stability and triggers defects in mitosis, suggesting that TBK1 functions as a mitotic kinase necessary for microtubule dynamics and mitosis.
Left–right asymmetric cell intercalation drives directional collective cell movement in epithelial morphogenesis
Authors: Sato Katsuhiko , Hiraiwa Tetsuya , Maekawa Emi , Isomura Ayako , Shibata Tatsuo , Kuranaga Erina 
Published: December 2015

AbstractMorphogenetic epithelial movement occurs during embryogenesis and drives complex tissue formation. However, how epithelial cells coordinate their unidirectional movement while maintaining epithelial integrity is unclear. Here we propose a novel mechanism for collective epithelial cell movement based on Drosophila genitalia rotation, in which epithelial tissue rotates clockwise around the genitalia. We found that this cell movement occurs autonomously and requires myosin II. The moving cells exhibit repeated left–right-biased junction remodelling, while maintaining adhesion with their neighbours, in association with a polarized myosin II distribution. Reducing myosinID, known to cause counter-clockwise epithelial-tissue movement, reverses the myosin II distribution. Numerical simulations revealed that a left–right asymmetry in cell intercalation is sufficient to induce unidirectional cellular movement. The cellular movement direction is also associated with planar cell-shape chirality. These findings support a model in which left–right asymmetric cell intercalation within an epithelial sheet drives collective cellular movement in the same direction.
Arp2/3-mediated F-actin formation controls regulated exocytosis in vivo
Authors: Tran Duy T. , Masedunskas Andrius , Weigert Roberto , Ten Hagen Kelly G. 
Published: December 2015

AbstractThe actin cytoskeleton plays crucial roles in many cellular processes, including regulated secretion. However, the mechanisms controlling F-actin dynamics in this process are largely unknown. Through 3D time-lapse imaging in a secreting organ, we show that F-actin is actively disassembled along the apical plasma membrane at the site of secretory vesicle fusion and re-assembled directionally on vesicle membranes. Moreover, we show that fusion pore formation and PIP2 redistribution precedes actin and myosin recruitment to secretory vesicle membranes. Finally, we show essential roles for the branched actin nucleators Arp2/3- and WASp in the process of secretory cargo expulsion and integration of vesicular membranes with the apical plasma membrane. Our results highlight previously unknown roles for branched actin in exocytosis and provide a genetically tractable system to image the temporal and spatial dynamics of polarized secretion in vivo.
DARPP-32 interaction with adducin may mediate rapid environmental effects on striatal neurons
Authors: Engmann Olivia , Giralt Albert , Gervasi Nicolas , Marion-Poll Lucile , Gasmi Laila , Filhol Odile , Picciotto Marina R. , Gilligan Diana , Greengard Paul , Nairn Angus C. , Hervé Denis , Girault Jean-Antoine 
Published: December 2015

AbstractEnvironmental enrichment has multiple effects on behaviour, including modification of responses to psychostimulant drugs mediated by striatal neurons. However, the underlying molecular and cellular mechanisms are not known. Here we show that DARPP-32, a hub signalling protein in striatal neurons, interacts with adducins, which are cytoskeletal proteins that cap actin filaments’ fast-growing ends and regulate synaptic stability. DARPP-32 binds to adducin MARCKS domain and this interaction is modulated by DARPP-32 Ser97 phosphorylation. Phospho-Thr75-DARPP-32 facilitates β-adducin Ser713 phosphorylation through inhibition of a cAMP-dependent protein kinase/phosphatase-2A cascade. Caffeine or 24-h exposure to a novel enriched environment increases adducin phosphorylation in WT, but not T75A mutant mice. This cascade is implicated in the effects of brief exposure to novel enriched environment on dendritic spines in nucleus accumbens and cocaine locomotor response. Our results suggest a molecular pathway by which environmental changes may rapidly alter responsiveness of striatal neurons involved in the reward system.
Cell cycle and p53 gate the direct conversion of human fibroblasts to dopaminergic neurons
Authors: Jiang Houbo , Xu Zhimin , Zhong Ping , Ren Yong , Liang Gaoyang , Schilling Haley A. , Hu Zihua , Zhang Yi , Wang Xiaomin , Chen Shengdi , Yan Zhen , Feng Jian 
Published: December 2015

AbstractThe direct conversion of fibroblasts to induced dopaminergic (iDA) neurons and other cell types demonstrates the plasticity of cell fate. The low efficiency of these relatively fast conversions suggests that kinetic barriers exist to safeguard cell-type identity. Here we show that suppression of p53, in conjunction with cell cycle arrest at G1 and appropriate extracellular environment, markedly increase the efficiency in the transdifferentiation of human fibroblasts to iDA neurons by Ascl1, Nurr1, Lmx1a and miR124. The conversion is dependent on Tet1, as G1 arrest, p53 knockdown or expression of the reprogramming factors induces Tet1 synergistically. Tet1 knockdown abolishes the transdifferentiation while its overexpression enhances the conversion. The iDA neurons express markers for midbrain DA neurons and have active dopaminergic transmission. Our results suggest that overcoming these kinetic barriers may enable highly efficient epigenetic reprogramming in general and will generate patient-specific midbrain DA neurons for Parkinson’s disease research and therapy.
Engulfment pathways promote programmed cell death by enhancing the unequal segregation of apoptotic potential
Authors: Chakraborty Sayantan , Lambie Eric J. , Bindu Samik , Mikeladze-Dvali Tamara , Conradt Barbara 
Published: December 2015

AbstractComponents of the conserved engulfment pathways promote programmed cell death in Caenorhabditis elegans (C. elegans) through an unknown mechanism. Here we report that the phagocytic receptor CED-1 mEGF10 is required for the formation of a dorsal–ventral gradient of CED-3 caspase activity within the mother of a cell programmed to die and an increase in the level of CED-3 protein within its dying daughter. Furthermore, CED-1 becomes enriched on plasma membrane regions of neighbouring cells that appose the dorsal side of the mother, which later forms the dying daughter. Therefore, we propose that components of the engulfment pathways promote programmed cell death by enhancing the polar localization of apoptotic factors in mothers of cells programmed to die and the unequal segregation of apoptotic potential into dying and surviving daughters. Our findings reveal a novel function of the engulfment pathways and provide a better understanding of how apoptosis is initiated during C. elegans development.
Elevated levels of TRF2 induce telomeric ultrafine anaphase bridges and rapid telomere deletions
Authors: Nera Bernadette , Huang Hui-Shun , Lai Thao , Xu Lifeng 
Published: December 2015

AbstractThe shelterin protein TRF2 is essential for chromosome-end protection. Depletion of TRF2 causes chromosome end-to-end fusions, initiating genomic instability that can be cancer promoting. Paradoxically, significant increased levels of TRF2 are observed in a subset of human cancers. Experimental overexpression of TRF2 has also been shown to induce telomere shortening, through an unknown mechanism. Here we report that TRF2 overexpression results in replication stalling in duplex telomeric repeat tracts and the subsequent formation of telomeric ultrafine anaphase bridges (UFBs), ultimately leading to stochastic loss of telomeric sequences. These TRF2 overexpression-induced telomere deletions generate chromosome fusions resembling those detected in human cancers and in mammalian cells containing critically shortened telomeres. Therefore, our findings have uncovered a second pathway by which altered TRF2 protein levels can induce end-to-end fusions. The observations also provide mechanistic insight into the molecular basis of genomic instability in tumour cells containing significantly increased TRF2 levels.
Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution
Authors: Kasar S. , Kim J. , Improgo R. , Tiao G. , Polak P. , Haradhvala N. , Lawrence M. S. , Kiezun A. , Fernandes S. M. , Bahl S. , Sougnez C. , Gabriel S. , Lander E. S. , Kim H. T. , Getz G. , Brown J. R. 
Published: December 2015

AbstractPatients with chromosome 13q deletion or normal cytogenetics represent the majority of chronic lymphocytic leukaemia (CLL) cases, yet have relatively few driver mutations. To better understand their genomic landscape, here we perform whole-genome sequencing on a cohort of patients enriched with these cytogenetic characteristics. Mutations in known CLL drivers are seen in only 33% of this cohort, and associated with normal cytogenetics and unmutated IGHV. The most commonly mutated gene in our cohort, IGLL5, shows a mutational pattern suggestive of activation-induced cytidine deaminase (AID) activity. Unsupervised analysis of mutational signatures demonstrates the activities of canonical AID (c-AID), leading to clustered mutations near active transcriptional start sites; non-canonical AID (nc-AID), leading to genome-wide non-clustered mutations, and an ageing signature responsible for most mutations. Using mutation clonality to infer time of onset, we find that while ageing and c-AID activities are ongoing, nc-AID-associated mutations likely occur earlier in tumour evolution.