bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cretaceous‐Paleogene Tectonics of the Pelagonian Zone: Inferences From Skopelos Island (Greece)
Authors: Porkoláb Kristóf , Willingshofer Ernst , Sokoutis Dimitrios , Creton Iverna , Kostopoulos Dimitrios , Wijbrans Jan 
Published: May 2019

AbstractWe have investigated subduction‐exhumation processes in the Pelagonian zone, exposed on the Northern Sporades islands (Aegean Sea) related to successive episodes of ocean continent and continent‐continent convergence through integrating multiscale structural analysis, metamorphic petrology, and white mica 40Ar/39Ar dating. Two major progressive phases of ductile deformation are documented, which are related to distinct episodes of tectonic burial and exhumation of the Pelagonian continental margin, which was facing the Neotethys/Vardar ocean. Review of existing data sets from neighboring regions shows that both deformation phases can be correlated along strike up to the Dinarides. The first phase of tectonic burial and exhumation (D1) is characterized by NW‐SE tectonic transport, greenschist facies metamorphism, and Early Cretaceous (~105‐135Ma) 40Ar/39 Ar white mica single fusion ages. D1 is correlated with the initial closure of the Vardar ocean by top‐to‐the‐W to NW ophiolite obduction and the underthrusting of the Pelagonian margin below the oceanic upper plate. Underthrusting was followed by exhumation and the deposition of Late Cretaceous‐Paleogene sediments. The second phase of burial and exhumation (D2) is characterized by NE‐SW tectonic transport, greenschist to blueschist facies metamorphism, and latest Cretaceous‐Early Eocene 40Ar/39 Ar white mica ages of S2 fabrics. Top‐to‐the‐SW shearing is correlated with the tectonic burial of the Pelagonian zone below the Eurasian continent (Rhodopia), while top‐to‐the‐NE shearing is attributed to subsequent extensional exhumation. D2 fabrics record low‐grade P‐T conditions suggesting that the decoupled cover formations exposed on Skopelos were incorporated in an accretionary wedge that formed above the subducting Pelagonian basement during Paleogene times.
The Importance of Interflow to Groundwater Recharge in a Snowmelt‐Dominated Headwater Basin
Authors: Carroll Rosemary W. H. , Deems Jeffrey S. , Niswonger Richard , Schumer Rina , Williams Kenneth H. 
Published: May 2019

AbstractUnderstanding the sensitivity of groundwater generation to climate in a mountain system is complicated by the tight coupling of snow dynamics to vegetation and topography. To address these feedbacks, we combine light detection and ranging (LiDAR)‐derived snow observations with an integrated hydrologic model to quantify spatially and temporally distributed water fluxes across varying climate conditions in a Colorado River headwater basin. Results indicate that annual groundwater flow is an important and stable source of stream water. However, interflow decreases during drought as a function increased plant water use and the relative fraction of groundwater to streams increases. Seasonal snowmelt and vegetation water use regulate small recharge rates in the lower portions of the basin, but snowmelt transported via interflow from high mountain ridges toward convergent topographic zones defines preferential recharge in the upper subalpine. Recharge in this zone appears decoupled from annual climate variability and resilient to drought.
Magnetic Field in the Martian Magnetosheath and the Application as an IMF Clock Angle Proxy
Authors: Dong Y. , Fang X. , Brain D. A. , Hurley D. M. , Halekas J. S. , Espley J. R. , Ramstad R. , Ruhunusiri S. , Jakosky B. M. 
Published: May 2019

AbstractWe present a study of the magnetic field in the Martian magnetosheath using data from the Mars Atmosphere and Volatile EvolutioN (MAVEN) mission and provide a proxy for the upstream interplanetary magnetic field (IMF) clock angles based on the sheath field directions. The magnetic field data from MAVEN taken in the sheath region are organized in the Mars Solar Electric field coordinate system and sorted by the IMF polarity. The sheath magnetic field distributions clearly illustrate the morphology of draped IMF around the planetary obstacle and show strong asymmetries between the quasi‐perpendicular and quasi‐parallel bow shock quadrants as well as a slight asymmetry between the +E and –E quadrants. We have also studied the effects of different drivers on the strengths and clock angles of the sheath magnetic field and find that the sheath field is strongly affected by upstream IMF and solar wind and that Martian crustal fields also have small contributions to the sheath magnetic field strength. Based on the morphology of the draped field in the sheath, we developed a simple IMF clock angle proxy as the clock angle of the orbital‐averaged sheath magnetic field, which works well under steady IMF conditions. This proxy has an error <44° for 75% of all instances. The uncertainty of the proxy depends on upstream conditions and spacecraft orbit geometry. We also provide estimates of the proxy uncertainty based on sheath magnetic field variability and proxy clock angle.
Alzheimer’s disease polygenic risk score as a predictor of conversion from mild-cognitive impairment
Authors: Chaudhury Sultan , Brookes Keeley J. , Patel Tulsi , Fallows Abigail , Guetta-Baranes Tamar , Turton James C. , Guerreiro Rita , Bras Jose , Hardy John , Francis Paul T. , Croucher Rebecca , Holmes Clive , Morgan Kevin , Thomas A. J. 
Published: May 2019

AbstractMild-cognitive impairment (MCI) occurs in up to one-fifth of individuals over the age of 65, with approximately a third of MCI individuals converting to dementia in later life. There is a growing necessity for early identification for those at risk of dementia as pathological processes begin decades before onset of symptoms. A cohort of 122 individuals diagnosed with MCI and followed up for a 36-month period for conversion to late-onset Alzheimer’s disease (LOAD) were genotyped on the NeuroChip array along with pathologically confirmed cases of LOAD and cognitively normal controls. Polygenic risk scores (PRS) for each individual were generated using PRSice-2, derived from summary statistics produced from the International Genomics of Alzheimer’s Disease Project (IGAP) genome-wide association study. Predictability models for LOAD were developed incorporating the PRS with APOE SNPs (rs7412 and rs429358), age and gender. This model was subsequently applied to the MCI cohort to determine whether it could be used to predict conversion from MCI to LOAD. The PRS model for LOAD using area under the precision-recall curve (AUPRC) calculated a predictability for LOAD of 82.5%. When applied to the MCI cohort predictability for conversion from MCI to LOAD was 61.0%. Increases in average PRS scores across diagnosis group were observed with one-way ANOVA suggesting significant differences in PRS between the groups (p < 0.0001). This analysis suggests that the PRS model for LOAD can be used to identify individuals with MCI at risk of conversion to LOAD.
Central role of IP3R2-mediated Ca2+ oscillation in self-renewal of liver cancer stem cells elucidated by high-signal ER sensor
Authors: Sun Cuiwei , Shui Bo , Zhao Wei , Liu Hui , Li Wenwen , Lee Jane C. , Doran Robert , Lee Frank K. , Sun Tao , Shen Qing Sunny , Wang Xianhua , Reining Shaun , Kotlikoff Michael I. , Zhang Zhiqian , Cheng Heping 
Published: May 2019

AbstractCa2+ oscillation is a system-level property of the cellular Ca2+-handling machinery and encodes diverse physiological and pathological signals. The present study tests the hypothesis that Ca2+ oscillations play a vital role in maintaining the stemness of liver cancer stem cells (CSCs), which are postulated to be responsible for cancer initiation and progression. We found that niche factor-stimulated Ca2+ oscillation is a signature feature of CSC-enriched Hep-12 cells and purified α2δ1+ CSC fractions from hepatocellular carcinoma cell lines. In Hep-12 cells, the Ca2+ oscillation frequency positively correlated with the self-renewal potential. Using a newly developed high signal, endoplasmic reticulum (ER) localized Ca2+ sensor GCaMP-ER2, we demonstrated CSC-distinctive oscillatory ER Ca2+ release controlled by the type 2 inositol 1,4,5-trisphosphate receptor (IP3R2). Knockdown of IP3R2 severely suppressed the self-renewal capacity of liver CSCs. We propose that targeting the IP3R2-mediated Ca2+ oscillation in CSCs might afford a novel, physiologically inspired anti-tumor strategy for liver cancer.
Kinesin-14 motor protein KIFC1 participates in DNA synthesis and chromatin maintenance
Authors: Wei Ya-Lan , Yang Wan-Xi 
Published: May 2019

AbstractThe nuclear localization signal (NLS) in kinesin-14 KIFC1 is associated with nuclear importins and Ran gradient, but detailed mechanism remains unknown. In this study, we found that KIFC1 proteins have specific transport characteristics during cell cycle. In the absence of KIFC1, cell cycle kinetics decrease significantly with a prolonged S phase. After KIFC1 overexpression, the duration of S phase becomes shorten. KIFC1 may transport the recombinant/replicate-related proteins into the nucleus, meanwhile avoiding excessive KIFC1 in the cytoplasm, which results in aberrant microtubule bundling. Interestingly, the deletion of kifc1 in human cells results in a higher ratio of aberrant nuclear membrane, and the degradation of lamin B and lamin A/C. We also found that kifc1 deletion leads to defects in metaphase mitotic spindle assembly, and then results in chromosome structural abnormality. The kifc1-/- cells finally form micronuclei in daughter cells, and results in aneuploidy and chromosome loss in cell cycle. In this study, we demonstrate that kinesin-14 KIFC1 proteins involve in regulating DNA synthesis in S phase, and chromatin maintenance in mitosis, and maintain cell growth in a nuclear transport-independent way.
Rack1 mediates Src binding to drug transporter P-glycoprotein and modulates its activity through regulating Caveolin-1 phosphorylation in breast cancer cells
Authors: Fan Yanling , Si Weiyao , Ji Wei , Wang Zhiyong , Gao Zicong , Tian Ran , Song Weijie , Zhang He , Niu Ruifang , Zhang Fei 
Published: May 2019

AbstractThe failure of chemotherapy and the emergence of multidrug resistance (MDR) are the major obstacles for effective therapy in locally advanced and metastatic breast cancer. Overexpression of the drug transporter P-glycoprotein (P-gp) in cancer cells is one of the main causes of MDR due to its ability to efflux anticancer drugs out of cells. Although the signaling node that regulates the expression of P-gp has been intensively investigated; the regulatory mechanism underlying P-gp transport activity remains obscure. Herein, we reported that Rack1 and tyrosine kinase Src confer drug resistance through modulating the transport function of P-gp without altering its protein level. We provide evidences that Rack1 and Src regulate P-gp activity by modulating caveolin-1 (Cav1) phosphorylation. Importantly, Rack1 acts as a signaling hub and mediates Src binding to P-gp, thereby facilitating the phosphorylation of Cav1 by Src and abolishing the inhibitory effect of Cav1 on P-gp. Taken together, our results demonstrate the pivotal roles of Rack1 and Src in modulating P-gp activity in drug-resistant cells. Our findings also provide novel insights into the mechanism regulating P-gp transport activity. Rack1 may represent a new target for the development of effective therapies for reversing drug resistance.
The cell-wide web coordinates cellular processes by directing site-specific Ca2+ flux across cytoplasmic nanocourses
Authors: Duan Jingxian , Navarro-Dorado Jorge , Clark Jill H. , Kinnear Nicholas P. , Meinke Peter , Schirmer Eric C. , Evans A. Mark 
Published: May 2019

AbstractCa2+ coordinates diverse cellular processes, yet how function-specific signals arise is enigmatic. We describe a cell-wide network of distinct cytoplasmic nanocourses with the nucleus at its centre, demarcated by sarcoplasmic reticulum (SR) junctions (≤400 nm across) that restrict Ca2+ diffusion and by nanocourse-specific Ca2+-pumps that facilitate signal segregation. Ryanodine receptor subtype 1 (RyR1) supports relaxation of arterial myocytes by unloading Ca2+ into peripheral nanocourses delimited by plasmalemma-SR junctions, fed by sarco/endoplasmic reticulum Ca2+ ATPase 2b (SERCA2b). Conversely, stimulus-specified increases in Ca2+ flux through RyR2/3 clusters selects for rapid propagation of Ca2+ signals throughout deeper extraperinuclear nanocourses and thus myocyte contraction. Nuclear envelope invaginations incorporating SERCA1 in their outer nuclear membranes demarcate further diverse networks of cytoplasmic nanocourses that receive Ca2+ signals through discrete RyR1 clusters, impacting gene expression through epigenetic marks segregated by their associated invaginations. Critically, this circuit is not hardwired and remodels for different outputs during cell proliferation.
Epigenetic dysregulation of enhancers in neurons is associated with Alzheimer’s disease pathology and cognitive symptoms
Authors: Li Peipei , Marshall Lee , Oh Gabriel , Jakubowski Jennifer L. , Groot Daniel , He Yu , Wang Ting , Petronis Arturas , Labrie Viviane 
Published: May 2019

AbstractEpigenetic control of enhancers alters neuronal functions and may be involved in Alzheimer’s disease (AD). Here, we identify enhancers in neurons contributing to AD by comprehensive fine-mapping of DNA methylation at enhancers, genome-wide. We examine 1.2 million CpG and CpH sites in enhancers in prefrontal cortex neurons of individuals with no/mild, moderate, and severe AD pathology (n = 101). We identify 1224 differentially methylated enhancer regions; most of which are hypomethylated at CpH sites in AD neurons. CpH methylation losses occur in normal aging neurons, but are accelerated in AD. Integration of epigenetic and transcriptomic data demonstrates a pro-apoptotic reactivation of the cell cycle in post-mitotic AD neurons. Furthermore, AD neurons have a large cluster of significantly hypomethylated enhancers in the DSCAML1 gene that targets BACE1. Hypomethylation of these enhancers in AD is associated with an upregulation of BACE1 transcripts and an increase in amyloid plaques, neurofibrillary tangles, and cognitive decline.
Development of an immunodeficient pig model allowing long-term accommodation of artificial human vascular tubes
Authors: Itoh Manabu , Mukae Yosuke , Kitsuka Takahiro , Arai Kenichi , Nakamura Anna , Uchihashi Kazuyoshi , Toda Shuji , Matsubayashi Kumika , Oyama Jun-ichi , Node Koichi , Kami Daisuke , Gojo Satoshi , Morita Shigeki , Nishida Takahiro , Nakayama Koichi , Kobayashi Eiji 
Published: May 2019

AbstractBefore they are used in the clinical setting, the effectiveness of artificially produced human-derived tissue-engineered medical products should be verified in an immunodeficient animal model, such as severe combined immunodeficient mice. However, small animal models are not sufficient to evaluate large-sized products for human use. Thus, an immunodeficient large animal model is necessary in order to properly evaluate the clinical efficacy of human-derived tissue-engineered products, such as artificial grafts. Here we report the development of an immunodeficient pig model, the operational immunodeficient pig (OIDP), by surgically removing the thymus and spleen, and creating a controlled immunosuppressive protocol using a combination of drugs commonly used in the clinical setting. We find that this model allows the long-term accommodation of artificial human vascular grafts. The development of the OIDP is an essential step towards a comprehensive and clinically relevant evaluation of human cell regeneration strategies at the preclinical stage.
Inhibition of tetrameric Patched1 by Sonic Hedgehog through an asymmetric paradigm
Authors: Qian Hongwu , Cao Pingping , Hu Miaohui , Gao Shuai , Yan Nieng , Gong Xin 
Published: May 2019

AbstractThe Hedgehog (Hh) pathway controls embryonic development and postnatal tissue maintenance and regeneration. Inhibition of Hh receptor Patched (Ptch) by the Hh ligands relieves suppression of signaling cascades. Here, we report the cryo-EM structure of tetrameric Ptch1 in complex with the palmitoylated N-terminal signaling domain of human Sonic hedgehog (ShhNp) at a 4:2 stoichiometric ratio. The structure shows that four Ptch1 protomers are organized as a loose dimer of dimers. Each dimer binds to one ShhNp through two distinct inhibitory interfaces, one mainly through the N-terminal peptide and the palmitoyl moiety of ShhNp and the other through the Ca2+-mediated interface on ShhNp. Map comparison reveals that the cholesteryl moiety of native ShhN occupies a recently identified extracellular steroid binding pocket in Ptch1. Our structure elucidates the tetrameric assembly of Ptch1 and suggests an asymmetric mode of action of the Hh ligands for inhibiting the potential cholesterol transport activity of Ptch1.
Increasing species sampling in chelicerate genomic-scale datasets provides support for monophyly of Acari and Arachnida
Authors: Lozano-Fernandez Jesus , Tanner Alastair R. , Giacomelli Mattia , Carton Robert , Vinther Jakob , Edgecombe Gregory D. , Pisani Davide 
Published: May 2019

AbstractChelicerates are a diverse group of arthropods, represented by such forms as predatory spiders and scorpions, parasitic ticks, humic detritivores, and marine sea spiders (pycnogonids) and horseshoe crabs. Conflicting phylogenetic relationships have been proposed for chelicerates based on both morphological and molecular data, the latter usually not recovering arachnids as a clade and instead finding horseshoe crabs nested inside terrestrial Arachnida. Here, using genomic-scale datasets and analyses optimised for countering systematic error, we find strong support for monophyletic Acari (ticks and mites), which when considered as a single group represent the most biodiverse chelicerate lineage. In addition, our analysis recovers marine forms (sea spiders and horseshoe crabs) as the successive sister groups of a monophyletic lineage of terrestrial arachnids, suggesting a single colonisation of land within Chelicerata and the absence of wholly secondarily marine arachnid orders.
Transforming activity of an oncoprotein-encoding circular RNA from human papillomavirus
Authors: Zhao Jiawei , Lee Eunice E. , Kim Jiwoong , Yang Rong , Chamseddin Bahir , Ni Chunyang , Gusho Elona , Xie Yang , Chiang Cheng-Ming , Buszczak Michael , Zhan Xiaowei , Laimins Laimonis , Wang Richard C. 
Published: May 2019

AbstractSingle-stranded circular RNAs (circRNAs), generated through ‘backsplicing’, occur more extensively than initially anticipated. The possible functions of the vast majority of circRNAs remain unknown. Virus-derived circRNAs have recently been described in gamma-herpesviruses. We report that oncogenic human papillomaviruses (HPVs) generate circRNAs, some of which encompass the E7 oncogene (circE7). HPV16 circE7 is detectable by both inverse RT-PCR and northern blotting of HPV16-transformed cells. CircE7 is N6-methyladenosine (m6A) modified, preferentially localized to the cytoplasm, associated with polysomes, and translated to produce E7 oncoprotein. Specific disruption of circE7 in CaSki cervical carcinoma cells reduces E7 protein levels and inhibits cancer cell growth both in vitro and in tumor xenografts. CircE7 is present in TCGA RNA-Seq data from HPV-positive cancers and in cell lines with only episomal HPVs. These results provide evidence that virus-derived, protein-encoding circular RNAs are biologically functional and linked to the transforming properties of some HPV.
Realization of high-efficiency fluorescent organic light-emitting diodes with low driving voltage
Authors: Salehi Amin , Dong Chen , Shin Dong-Hun , Zhu Liping , Papa Christopher , Thy Bui Anh , Castellano Felix N. , So Franky 
Published: May 2019

AbstractIt is commonly accepted that a full bandgap voltage is required to achieving efficient electroluminescence (EL) in organic light-emitting diodes. In this work, we demonstrated organic molecules with a large singlet-triplet splitting can achieve efficient EL at voltages below the bandgap voltage. The EL originates from delayed fluorescence due to triplet fusion. Finally, in spite of a lower quantum efficiency, a blue fluorescent organic light-emitting diode having a power efficiency higher than some of the best thermally activated delayed fluorescent and phosphorescent blue organic light-emitting diodes is demonstrated. The current findings suggest that leveraging triplet fusion from purely organic molecules in organic light-emitting diode materials offers an alternative route to achieve stable and high efficiency blue organic light-emitting diodes.
Collective cell migration and metastases induced by an epithelial-to-mesenchymal transition in Drosophila intestinal tumors
Authors: Campbell Kyra , Rossi Fabrizio , Adams Jamie , Pitsidianaki Ioanna , Barriga Francisco M. , Garcia-Gerique Laura , Batlle Eduard , Casanova Jordi , Casali Andreu 
Published: May 2019

AbstractMetastasis underlies the majority of cancer-related deaths yet remains poorly understood due, in part, to the lack of models in vivo. Here we show that expression of the EMT master inducer Snail in primary adult Drosophila intestinal tumors leads to the dissemination of tumor cells and formation of macrometastases. Snail drives an EMT in tumor cells, which, although retaining some epithelial markers, subsequently break through the basal lamina of the midgut, undergo a collective migration and seed polyclonal metastases. While metastases re-epithelialize over time, we found that early metastases are remarkably mesenchymal, discarding the requirement for a mesenchymal-to-epithelial transition for early stages of metastatic growth. Our results demonstrate the formation of metastases in adult flies, and identify a key role for partial-EMTs in driving it. This model opens the door to investigate the basic mechanisms underlying metastasis, in a powerful in vivo system suited for rapid genetic and drug screens.
Atomic resolution electron microscopy in a magnetic field free environment
Authors: Shibata N. , Kohno Y. , Nakamura A. , Morishita S. , Seki T. , Kumamoto A. , Sawada H. , Matsumoto T. , Findlay S. D. , Ikuhara Y. 
Published: May 2019

AbstractAtomic-resolution electron microscopes utilize high-power magnetic lenses to produce magnified images of the atomic details of matter. Doing so involves placing samples inside the magnetic objective lens, where magnetic fields of up to a few tesla are always exerted. This can largely alter, or even destroy, the magnetic and physical structures of interest. Here, we describe a newly developed magnetic objective lens system that realizes a magnetic field free environment at the sample position. Combined with a higher-order aberration corrector, we achieve direct, atom-resolved imaging with sub-Å spatial resolution with a residual magnetic field of less than 0.2 mT at the sample position. This capability enables direct atom-resolved imaging of magnetic materials such as silicon steels. Removing the need to subject samples to high magnetic field environments enables a new stage in atomic resolution electron microscopy that realizes direct, atomic-level observation of samples without unwanted high magnetic field effects.