bluuebunny/crossref_metadata_2025_split huggingface dataset:
PINK1/Parkin-mediated mitophagy is activated in cisplatin nephrotoxicity to protect against kidney injury
Authors: Wang Ying , Tang Chengyuan , Cai Juan , Chen Guochun , Zhang Dongshan , Zhang Zhuohua , Dong Zheng 
Published: November 2018

AbstractCisplatin is a widely used chemotherapeutic drug with notorious toxicity in the kidneys, which involves mitochondrial dysfunction and damage in renal tubular cells. Mitophagy is a form of selective autophagy that removes damaged or dysfunctional mitochondria to maintain cellular homeostasis. In this study, we have used mouse and cell models to examine the role and regulation of mitophagy in cisplatin nephrotoxicity. Cisplatin treatment was associated with the activation of autophagy and mitophagy. Rapamycin, a pharmacological inhibitor of mTOR, stimulated autophagy and mitophagy, and alleviated the development of cisplatin nephrotoxicity. PINK1 and Parkin were increased in kidney tissues during cisplatin treatment of mice. In PINK1 or Parkin gene knockout mouse models, both basal and cisplatin-induced mitophagy in kidneys were defective. Compared with wild-type littermates, PINK1 and Parkin knockout mice showed more severe renal functional loss, tissue damage, and apoptosis during cisplatin treatment. The results suggest that PINK1/Parkin-mediated mitophagy is activated in cisplatin nephrotoxicity and has a protective role against kidney injury.
The SGK3-triggered ubiquitin–proteasome degradation of podocalyxin (PC) and ezrin in podocytes was associated with the stability of the PC/ezrin complex
Authors: Yuan Ya-Pei , Zhao Hong , Peng Li-Qin , Li Zi-Fang , Liu Song , Yuan Cheng-Yan , Mwamunyi Mercy-Julian , Pearce David , Yao Li-Jun 
Published: November 2018

AbstractPodocyte damage is commonly accompanied by destabilization of the podocalyxin (PC)/ezrin complex. Serum- and glucocorticoid-inducible kinase 3 (SGK3) plays a role in the maintenance of podocyte function, but the details of this role are poorly understood. Herein we demonstrated that SGK3 and its downstream target protein neural precursor cell expressed developmentally downregulated protein 4 subtype 2 (Nedd4-2) triggered PC and ezrin interaction. In adriamycin (ADR)-induced nephritic mice, and after puromycin aminonucleoside (PAN)-induced podocyte damage in vitro, PC and ezrin protein expression levels decreased significantly, while Nedd4-2 activity increased. Moreover, PAN treatment increased PC and ezrin ubiquitination and decreased PC/ezrin interaction in cultured mouse podocytes. The downregulation of SGK3 activity in mouse podocytes resulted in decreased PC and ezrin protein expression and increased the ubiquitin–proteasome degradation of PC and ezrin. Furthermore, upregulation of SGK3 activity mostly reversed the PAN-induced decrease in PC and ezrin protein expression. Overexpression of Nedd4-2 led to decreased ezrin protein expression via the upregulation of ezrin ubiquitination. In contrast, Nedd4-2 knockdown resulted in increased ezrin protein expression but decreased ezrin ubiquitination. In PC-transfected human embryonic kidney (HEK293T) cells, SGK3 activity downregulation and Nedd4-2 overexpression resulted in decreased PC/ezrin interaction. These results suggested that SGK3 triggers the ubiquitin–proteasome degradation of PC and ezrin, while the SGK3/Nedd4-2 signaling pathway regulates ezrin, but not PC, ubiquitination. Thus SGK3 helps to regulate podocyte function by maintaining the stability of the PC/ezrin complex.
Dynamic ubiquitylation of Sox2 regulates proteostasis and governs neural progenitor cell differentiation
Authors: Cui Chun-Ping , Zhang Yuan , Wang Chanjuan , Yuan Fang , Li Hongchang , Yao Yuying , Chen Yuhan , Li Chunnan , Wei Wenyi , Liu Cui Hua , He Fuchu , Liu Yan , Zhang Lingqiang 
Published: November 2018

AbstractSox2 is a key transcriptional factor for maintaining pluripotency of stem cells. Sox2 deficiency causes neurodegeneration and impairs neurogenesis. Although the transcriptional regulation of Sox2 has been extensively studied, the mechanisms that control Sox2 protein turnover are yet to be clarified. Here we show that the RING-finger ubiquitin ligase complex CUL4ADET1-COP1 and the deubiquitylase OTUD7B govern Sox2 protein stability during neural progenitor cells (NPCs) differentiation. Sox2 expression declines concordantly with OTUD7B and reciprocally with CUL4A and COP1 levels upon NPCs differentiation. COP1, as the substrate receptor, interacts directly with and ubiquitylates Sox2, while OTUD7B removes polyUb conjugates from Sox2 and increases its stability. COP1 knockdown stabilizes Sox2 and prevents differentiation, while OTUD7B knockdown destabilizes Sox2 and induces differentiation. Thus, CUL4ADET1-COP1 and OTUD7B exert opposite roles in regulating Sox2 protein stability at the post-translational level, which represents a critical regulatory mechanism involved in the maintenance and differentiation of NPCs.
Overcoming EGFRG724S-mediated osimertinib resistance through unique binding characteristics of second-generation EGFR inhibitors
Authors: Fassunke Jana , Müller Fabienne , Keul Marina , Michels Sebastian , Dammert Marcel A. , Schmitt Anna , Plenker Dennis , Lategahn Jonas , Heydt Carina , Brägelmann Johannes , Tumbrink Hannah L. , Alber Yannic , Klein Sebastian , Heimsoeth Alena , Dahmen Ilona , Fischer Rieke N. , Scheffler Matthias , Ihle Michaela A. , Priesner Vanessa , Scheel Andreas H. , Wagener Svenja , Kron Anna , Frank Konrad , Garbert Katia , Persigehl Thorsten , Püsken Michael , Haneder Stefan , Schaaf Bernhard , Rodermann Ernst , Engel-Riedel Walburga , Felip Enriqueta , Smit Egbert F. , Merkelbach-Bruse Sabine , Reinhardt H. Christian , Kast Stefan M. , Wolf Jürgen , Rauh Daniel , Büttner Reinhard , Sos Martin L. 
Published: November 2018

AbstractThe emergence of acquired resistance against targeted drugs remains a major clinical challenge in lung adenocarcinoma patients. In a subgroup of these patients we identified an association between selection of EGFRT790M-negative but EGFRG724S-positive subclones and osimertinib resistance. We demonstrate that EGFRG724S limits the activity of third-generation EGFR inhibitors both in vitro and in vivo. Structural analyses and computational modeling indicate that EGFRG724S mutations may induce a conformation of the glycine-rich loop, which is incompatible with the binding of third-generation TKIs. Systematic inhibitor screening and in-depth kinetic profiling validate these findings and show that second-generation EGFR inhibitors retain kinase affinity and overcome EGFRG724S-mediated resistance. In the case of afatinib this profile translates into a robust reduction of colony formation and tumor growth of EGFRG724S-driven cells. Our data provide a mechanistic basis for the osimertinib-induced selection of EGFRG724S-mutant clones and a rationale to treat these patients with clinically approved second-generation EGFR inhibitors.
Basal freeze-on generates complex ice-sheet stratigraphy
Authors: Leysinger Vieli G. J.-M. C. , Martín C. , Hindmarsh R. C. A. , Lüthi M. P. 
Published: November 2018

AbstractLarge, plume-like internal ice-layer-structures have been observed in radar images from both Antarctica and Greenland, rising from the ice-sheet base to up to half of the ice thickness. Their origins are not yet understood. Here, we simulate their genesis by basal freeze-on using numerical ice-flow modelling and analyse the transient evolution of the emerging ice-plume and the surrounding ice-layer structure as a function of both freeze-on rate and ice flux. We find good agreement between radar observations, modelled ice-plume geometry and internal layer structure, and further show that plume height relates primarily to ice-flux and only secondarily to freeze-on. An in-depth analysis, performed for Northern Greenland of observed spatial plume distribution related to ice flow, basal topography and water availability supports our findings regarding ice flux and suggests freeze-on is controlled by ascending subglacial water flow. Our results imply that widespread basal freeze-on strongly affects ice stratigraphy and consequently ice-core interpretations.
Molecular structure of promoter-bound yeast TFIID
Authors: Kolesnikova Olga , Ben-Shem Adam , Luo Jie , Ranish Jeff , Schultz Patrick , Papai Gabor 
Published: November 2018

AbstractTranscription preinitiation complex assembly on the promoters of protein encoding genes is nucleated in vivo by TFIID composed of the TATA-box Binding Protein (TBP) and 13 TBP-associate factors (Tafs) providing regulatory and chromatin binding functions. Here we present the cryo-electron microscopy structure of promoter-bound yeast TFIID at a resolution better than 5 Å, except for a flexible domain. We position the crystal structures of several subunits and, in combination with cross-linking studies, describe the quaternary organization of TFIID. The compact tri lobed architecture is stabilized by a topologically closed Taf5-Taf6 tetramer. We confirm the unique subunit stoichiometry prevailing in TFIID and uncover a hexameric arrangement of Tafs containing a histone fold domain in the Twin lobe.
Gene inversion potentiates bacterial evolvability and virulence
Authors: Merrikh Christopher N. , Merrikh Houra 
Published: November 2018

AbstractMost bacterial genes are encoded on the leading strand, co-orienting the movement of the replication machinery with RNA polymerases. This bias reduces the frequency of detrimental head-on collisions between the two machineries. The negative outcomes of these collisions should lead to selection against head-on alleles, maximizing genome co-orientation. Our findings challenge this model. Using the GC skew calculation, we reveal the evolutionary inversion record of all chromosomally encoded genes in multiple divergent bacterial pathogens. Against expectations, we find that a large number of co-oriented genes have inverted to the head-on orientation, presumably increasing the frequency of head-on replication-transcription conflicts. Furthermore, we find that head-on genes, (including key antibiotic resistance and virulence genes) have higher rates of non-synonymous mutations and are more frequently under positive selection (dN/dS > 1). Based on these results, we propose that spontaneous gene inversions can increase the evolvability and pathogenic capacity of bacteria through head-on replication-transcription collisions.
Epithelial cells release adenosine to promote local TNF production in response to polarity disruption
Authors: Poernbacher Ingrid , Vincent Jean-Paul 
Published: November 2018

AbstractDisruption of epithelial integrity contributes to chronic inflammatory disorders through persistent activation of stress signalling. Here we uncover a mechanism whereby disruption of apico-basal polarity promotes stress signalling. We show that depletion of Scribbled (Scrib), a baso-lateral determinant, causes epithelial cells to release adenosine through equilibrative channels into the extracellular space. Autocrine activation of the adenosine receptor leads to transcriptional upregulation of TNF, which in turn boosts the activity of JNK signalling. Thus, disruption of cell polarity feeds into a well-established stress pathway through the intermediary of an adenosine signalling branch. Although this regulatory input could help ensuring an effective response to acute polarity stress, we suggest that it becomes deleterious in situations of low-grade chronic disruption by provoking a private inflammatory-like TNF-driven response within the polarity-deficient epithelium.
Modern slavery and the race to fish
Authors: Tickler David , Meeuwig Jessica J. , Bryant Katharine , David Fiona , Forrest John A. H. , Gordon Elise , Larsen Jacqueline Joudo , Oh Beverly , Pauly Daniel , Sumaila Ussif R. , Zeller Dirk 
Published: November 2018

AbstractMarine fisheries are in crisis, requiring twice the fishing effort of the 1950s to catch the same quantity of fish, and with many fleets operating beyond economic or ecological sustainability. A possible consequence of diminishing returns in this race to fish is serious labour abuses, including modern slavery, which exploit vulnerable workers to reduce costs. Here, we use the Global Slavery Index (GSI), a national-level indicator, as a proxy for modern slavery and labour abuses in fisheries. GSI estimates and fisheries governance are correlated at the national level among the major fishing countries. Furthermore, countries having documented labour abuses at sea share key features, including higher levels of subsidised distant-water fishing and poor catch reporting. Further research into modern slavery in the fisheries sector is needed to better understand how the issue relates to overfishing and fisheries policy, as well as measures to reduce risk in these labour markets.
Whole body PD-1 and PD-L1 positron emission tomography in patients with non-small-cell lung cancer
Authors: Niemeijer A. N. , Leung D. , Huisman M. C. , Bahce I. , Hoekstra O. S. , van Dongen G. A. M. S. , Boellaard R. , Du S. , Hayes W. , Smith R. , Windhorst A. D. , Hendrikse N. H. , Poot A. , Vugts D. J. , Thunnissen E. , Morin P. , Lipovsek D. , Donnelly D. J. , Bonacorsi S. J. , Velasquez L. M. , de Gruijl T. D. , Smit E. F. , de Langen A. J. 
Published: November 2018

AbstractPD-L1 immunohistochemistry correlates only moderately with patient survival and response to PD-(L)1 treatment. Heterogeneity of tumor PD-L1 expression might limit the predictive value of small biopsies. Here we show that tumor PD-L1 and PD-1 expression can be quantified non-invasively using PET-CT in patients with non-small-cell lung cancer. Whole body PD-(L)1 PET-CT reveals significant tumor tracer uptake heterogeneity both between patients, as well as within patients between different tumor lesions.
PRKAA1/AMPKα1-driven glycolysis in endothelial cells exposed to disturbed flow protects against atherosclerosis
Authors: Yang Qiuhua , Xu Jiean , Ma Qian , Liu Zhiping , Sudhahar Varadarajan , Cao Yapeng , Wang Lina , Zeng Xianqiu , Zhou Yaqi , Zhang Min , Xu Yiming , Wang Yong , Weintraub Neal L. , Zhang Chunxiang , Fukai Tohru , Wu Chaodong , Huang Lei , Han Zhen , Wang Tao , Fulton David J. , Hong Mei , Huo Yuqing 
Published: November 2018

AbstractIncreased aerobic glycolysis in endothelial cells of atheroprone areas of blood vessels has been hypothesized to drive increased inflammation and lesion burden but direct links remain to be established. Here we show that endothelial cells exposed to disturbed flow in vivo and in vitro exhibit increased levels of protein kinase AMP-activated (PRKA)/AMP-activated protein kinases (AMPKs). Selective deletion of endothelial Prkaa1, coding for protein kinase AMP-activated catalytic subunit alpha1, reduces glycolysis, compromises endothelial cell proliferation, and accelerates the formation of atherosclerotic lesions in hyperlipidemic mice. Rescue of the impaired glycolysis in Prkaa1-deficient endothelial cells through Slc2a1 overexpression enhances endothelial cell viability and integrity of the endothelial cell barrier, and reverses susceptibility to atherosclerosis. In human endothelial cells, PRKAA1 is upregulated by disturbed flow, and silencing PRKAA1 reduces glycolysis and endothelial viability. Collectively, these results suggest that increased glycolysis in the endothelium of atheroprone arteries is a protective mechanism.
Magnetically driven orbital-selective insulator–metal transition in double perovskite oxides
Authors: Chen Hanghui 
Published: November 2018

AbstractInteraction-driven metal–insulator transitions or Mott transitions are widely observed in condensed matter systems. In multi-orbital systems, many-body physics is richer in which an orbital-selective metal–insulator transition is an intriguing and unique phenomenon. Here we use first-principles calculations to show that a magnetic transition (from paramagnetic to long-range magnetically ordered) can simultaneously induce an orbital-selective insulator–metal transition in rock-salt ordered double perovskite oxidesA2BB′O6, whereBis a non-magnetic ion (Y3+and Sc3+) andB′ a magnetic ion with ad3electronic configuration (Ru5+and Os5+). The orbital-selectivity originates from geometrical frustration of a face-centered-cubic lattice on which the magnetic ionsB′ reside. Including realistic structural distortions and spin-orbit interaction do not affect the transition. The predicted orbital-selective transition naturally explains the anomaly observed in the electric resistivity of Sr2YRuO6. Implications of other available experimental data are also discussed. This work shows that by exploiting geometrical frustration on non-bipartite lattices, new electronic/magnetic/orbital-coupled phase transitions can occur in correlated materials that are in the vicinity of metal–insulator phase boundary.
Bio-inspired Z-scheme g-C3N4/Ag2CrO4 for efficient visible-light photocatalytic hydrogen generation
Authors: Che Yuping , Lu Bingxin , Qi Qi , Chang Huaiqiu , Zhai Jin , Wang Kefeng , Liu Zhaoyue 
Published: November 2018

AbstractDue to low charge separation efficiency and poor stability, it is usually difficult for single-component photocatalysts such as graphitic carbon nitride (g-C3N4) and silver chromate (Ag2CrO4) to fulfill photocatalytic hydrogen production efficiently. Z-scheme charge transport mechanism that mimics the photosynthesis in nature is an effective way to solve the above problems. Inspired by photosynthesis, we report Ag2CrO4 nanoparticles-decorated g-C3N4 nanosheet as an efficient photocatalyst for hydrogen evolution reaction (HER) with methanol as sacrificial agent. The formation of Z-scheme g-C3N4/Ag2CrO4 nanosheets photocatalysts could inhibit the recombination of photogenerated electron-hole pairs, promote the generation of hydrogen by photosplitting of water. The experiment results indicate that g-C3N4/Ag2CrO4 nanocomposites present enhanced photocatalytic activity and stability in the H2 evolution of water splitting. And the nanocomposites g-C3N4/Ag2CrO4(23.1%) show the 14 times HER efficiency compared to that of bare g-C3N4.
Dynamic recognition and linkage specificity in K63 di-ubiquitin and TAB2 NZF domain complex
Authors: Moritsugu Kei , Nishi Hafumi , Inariyama Keiichi , Kobayashi Masanori , Kidera Akinori 
Published: November 2018

AbstractPoly-ubiquitin (poly-Ub) is involved in various cellular processes through the linkage-specific recognition of Ub-binding domains (UBD). In this study, using molecular dynamics (MD) simulation together with an enhanced sampling method, we demonstrated that K63-linked di-Ub recognizes the NZF domain of TAB2, a zinc finger UBD, in an ensemble of highly dynamic structures that form from the weak interactions between UBD and the flexible linker connecting the two Ubs. However, the K63 di-Ub/TAB2 NZF complex showed a much more compact and stable ensemble than the non-native complexes, linear di-Ub/TAB2 NZF and K33 di-Ub/TAB2 NZF, that were modeled from linear di-Ub/HOIL-1L NZF and K33 di-Ub/TRABID NZF1, respectively. We further demonstrated the importance of the length and position of the Ub-Ub linker in the results of MD simulations of K63 di-Ub/TAB2 NZF by changing the Ub linkage from the native K63 to four different non-native linkages, linear, K6, K11, and K48, while maintaining inter-molecular contacts in the native complex. No systems with non-native linkage maintained the native binding configuration. These simulation results provide an atomistic picture of the linkage specific recognition of poly-Ubs leading to the biological functions such as cellular colocalization of various component proteins in the signal transduction pathways.
Conserved Noncoding Sequences Boost ADR1 and SP1 Regulated Human Swiprosin-1 Promoter Activity
Authors: Thylur Ramesh P. , Ahn Sung Yong , Jung Eunhea , Jun Chang-Duk , Hyun Young-Min 
Published: November 2018

AbstractSwiprosin-1 is expressed in various types of cells or tissues of different species. To investigate the mechanisms underlying Swiprosin-1 expression pattern, we analyzed the promoter activity of 2-kilobase genomic sequences located at 5′ flanking region of the Swiprosin-1 gene. The −2000/+41 bp of 5′ flanking untranslated promoter region of Swiprosin-1 gene was constitutively transactivated without significant effect of PMA, A23187, or PMA/A23187 stimulation in Jurkat T cells. Further, we identified 5′ deletant of proximal promoter region (−100/+41 to −70/+41) plays a pivotal role in activating the Swiprosin-1 gene in Jurkat T cells. Our studies also verified that ADR1 and Sp1 transcription factors were located between −70 and -100 locus of 5′ flanking proximal promoter region, which is critical for the Swiprosin-1 promoter activity. ADR1 and Sp1 were shown to bind the regions of −82, −79, −76, −73 and −70 and; −79, −78 and −77, respectively, within the proximal promoter region of Swiprosin-1. Finally conserved noncoding sequences (CNS) -1, -2 and -3 were located between the exon 1 and exon 2 of Swiprosin-1 gene and synergistically transactivated the Swiprosin-1 promoter. In summary, Swiprosin-1 was constitutively expressed in Jurkat T cells by the coordinate action of ADR1 and SP1 transcription factors at the transcriptional level and CNS further boost the proximal region of Swiprosin-1 promoter activity. Our findings provide novel insights that the transcriptional regulation of Swiprosin-1 by targeting ADR1 and Sp1 binding sites may be helpful in exploring novel therapeutic strategies for advanced immune or other disorders.
Evidences for a shared history for spectacled salamanders, haplotypes and climate
Authors: Iannella Mattia , D’Alessandro Paola , Biondi Maurizio 
Published: November 2018

AbstractThe so-called glacial refugia, formed during the Pleistocene climatic oscillations, played a major role in shaping the distribution of European species, triggering migrations or isolating populations. Many of these events were recently investigated by genetic data, mainly for the European Last Glacial stage, in the Iberic, Italian and Greek-Balkan peninsulas. The amphibian genus Salamandrina, the most ancient living salamandrid lineage, was widespread in Europe until the climatic oscillations of Miocene probably forced it to shelter in the only suitable territory at that time, the Apennines. Nowadays this genus is endemic of peninsular Italy with two parapatric species, S. perspicillata and S. terdigitata, sharing an area of secondary contact formed after the Last Glacial Maximum. Climate is generally identified as the key factor for the interpretation of genetic data. In this research, we directly measure climate influences on the two Salamandrina known species through Ensemble Modelling techniques and post-modelling GIS analyses, integrating updated genetic data in this process. Our results confirm the hypotheses of southwards (and subsequent northwards) shifts, identify glacial refugia and corridors used for the post-glacial re-colonization. Finally, we map a contact zone deserving more sampling effort to disentangle the introgression and hybridization observed.