bluuebunny/crossref_metadata_2025_split huggingface dataset:
Psychometric Properties of the Children’s Version of the Spence Children’s Anxiety Scale (SCAS) in a Spanish Clinical Sample
Authors: Forcadell Eduard , Medrano Laura , Garcia-Delgar Blanca , Fernández-Martínez Iván , Orgilés Mireia , García Carolina , Lázaro Luisa , Lera-Miguel Sara 
Published: October 2020

Abstract
The Spence Children’s Anxiety Scale (SCAS) has demonstrated good psychometric properties in several countries and cultures. Nevertheless, most of the previous studies that explore these properties have combined clinical and community samples. We aimed to validate the Spanish version of the SCAS in a large clinical sample (N = 130) of children and adolescents. The Spanish adaptation of the SCAS showed good internal consistency for the total scale, and good test-retest reliability for all the subscales. Furthermore, its convergent and discriminant validity were supported by significant correlations with other anxiety questionnaires (Screen for Child Anxiety Related Emotional Disorders [SCARED], Youth Self-Report [YSR] subscales for anxiety disorders and internalizing symptomatology), and lower or non-significant correlations with depression symptoms and externalizing symptoms scales respectively. For the first time in a purely clinical sample, the original factor structure of the SCAS based on six correlated factors was confirmed. Future studies need to evaluate whether the factorial structure of the present instrument is the most suitable for use in clinical populations.
Estimation of Physiological Factors Controlling Carbon Isotope Fractionation in Coccolithophores in Photic Zone and Core‐Top Samples
Authors: Hernández‐Almeida Iván , Krumhardt Kristen M. , Zhang Hongrui , Stoll Heather M. 
Published: October 2020

AbstractEstimates of past pCO2 prior to ice‐core records have often been sought by measuring carbon isotopic fractionation during photosynthesis (Ɛp) in alkenone‐producing algae present in the fossil record. Photic zone and core‐top Ɛp show strong latitudinal gradients, which have been interpreted as an effect of growth rate. The factor b, used in previous studies to account for the changes in growth rate, shows high dependence on [CO2]aq in culture experiments, making difficult the deconvolution of nutrients versus other effects in the field. We combine coccolithophore growth rate output from a global model, limited by sea surface temperature (SST) and [PO43−] with a statistical model that include [CO2]aq, cell size and light to predict Ɛp, and examine the influence of different environmental and physiological variables on the observed expression of Ɛp in field samples. Back calculations of the growth rate necessary to match the observed Ɛp in photic zone and core‐top samples using the statistical model show high correlation with modeled growth rates using [PO43−] and SST in temperate regions. For Southern Ocean and tropical upwelling regions, with colder and warmer SST, respectively, there might be additional factors controlling growth rate not accounted for in the model, such as grazing or nutrient recycling. We evaluate the potential to reconstruct past growth rates using planktonic foraminifera‐ and coccolithophore‐based proxies related to water column structure. We found best application of these proxies as potential indicators of past [PO43−], which can subsequently be used in combination with proxy temperature, to estimate past coccolithophore growth rates.
P/Ca in Carbonates as a Proxy for Alkalinity and Phosphate Levels
Authors: Ingalls Miquela , Blättler Clara L. , Higgins John A. , Magyar John S. , Eiler John M. , Fischer Woodward W. 
Published: October 2020

AbstractUnderstanding mechanisms, rates, and drivers of past carbonate formation provides insight into the chemical evolution of Earth's oceans and atmosphere. We paired geological observations with elemental and isotope geochemistry to test potential proxies for calcium‐to‐alkalinity ratios (Ca:ALK). Across diverse carbonate facies from Pleistocene closed‐basin lakes in Owens Valley, CA, we observed less δ44/40Ca variation than theoretically predicted (>0.75‰) for the very low Ca:ALK in these systems. Carbonate clumped isotope disequilibria implied rapid carbonate growth—kinetic isotope effects, combined with the diverse carbonate minerals present, complicated the interpretation of δ44/40Ca as a paleoalkalinity proxy. In contrast, we observed that the high phosphate concentrations are recorded by shoreline and lake bottom carbonates formed in 11 Pleistocene lakes at orders of magnitude greater concentrations than in marine carbonates. Because the maximum phosphate content of water depends on Ca:ALK, we propose that carbonate P/Ca can inform phosphate levels and thereby Ca:ALK of aqueous environments in the carbonate record.
Application of Constitutive Friction Laws to Glacier Seismicity
Authors: Zoet L. K. , Ikari M. J. , Alley R. B. , Marone C. , Anandakrishnan S. , Carpenter B. M. , Scuderi M. M. 
Published: October 2020

AbstractWhile analysis of glacial seismicity continues to be a widely used method for interpreting glacial processes, the underlying mechanics controlling glacial stick‐slip seismicity remain speculative. Here, we report on laboratory shear experiments of debris‐laden ice slid over a bedrock asperity under carefully controlled conditions. By modifying the elastic loading stiffness, we generated the first laboratory icequakes. Our work represents the first comprehensive lab observations of unstable ice‐slip events and replicates several seismological field observations of glacier slip, such as slip velocity, stress drop, and the relationship between stress drop and recurrence interval. We also observe that stick‐slips initiate above a critical driving velocity and that stress drop magnitude decreases with further increases in velocity, consistent with friction theory and rock‐on‐rock friction laboratory experiments. Our results demonstrate that glacier slip behavior can be accurately predicted by the constitutive rate‐and‐state friction laws that were developed for rock friction.
Breaking the Ice: Identifying Hydraulically Forced Crevassing
Authors: Hudson T. S. , Brisbourne A. M. , White R. S. , Kendall J. M. , Arthern R. , Smith A. M. 
Published: October 2020

AbstractHydraulically forced crevassing is thought to reduce the stability of ice shelves and ice sheets, affecting structural integrity and providing pathways for surface meltwater to the bed. It can cause ice shelves to collapse and ice sheets to accelerate into the ocean. However, direct observations of the hydraulically forced crevassing process remain elusive. Here we report a novel method and observations that use icequakes to directly observe crevassing and determine the role of hydrofracture. Crevasse icequake depths from seismic observations are compared to a theoretically derived maximum dry crevasse depth. We observe icequakes below this depth, suggesting hydrofracture. Furthermore, icequake source mechanisms provide insight into the fracture process, with predominantly opening cracks observed, which have opening volumes of hundredths of a cubic meter. Our method and findings provide a framework for studying a critical process that is key for the stability of ice shelves and ice sheets and, therefore, future sea level rise projections.
Formyl peptide receptors in the mucosal immune system
Authors: Jeong Yu Sun , Bae Yoe-Sik 
Published: October 2020

AbstractFormyl peptide receptors (FPRs) belong to the G protein-coupled receptor (GPCR) family and are well known as chemotactic receptors and pattern recognition receptors (PRRs) that recognize bacterial and mitochondria-derived formylated peptides. FPRs are also known to detect a wide range of ligands, including host-derived peptides and lipids. FPRs are highly expressed not only in phagocytes such as neutrophils, monocytes, and macrophages but also in nonhematopoietic cells such as epithelial cells and endothelial cells. Mucosal surfaces, including the gastrointestinal tract, the respiratory tract, the oral cavity, the eye, and the reproductive tract, separate the external environment from the host system. In mucosal surfaces, the interaction between the microbiota and host cells needs to be strictly regulated to maintain homeostasis. By sharing the same FPRs, immune cells and epithelial cells may coordinate pathophysiological responses to various stimuli, including microbial molecules derived from the normal flora. Accumulating evidence shows that FPRs play important roles in maintaining mucosal homeostasis. In this review, we summarize the roles of FPRs at mucosal surfaces.
Inhibiting insulin and mTOR signaling by afatinib and crizotinib combination fosters broad cytotoxic effects in cutaneous malignant melanoma
Authors: Das Ishani , Chen Huiqin , Maddalo Gianluca , Tuominen Rainer , Rebecca Vito W. , Herlyn Meenhard , Hansson Johan , Davies Michael A. , Egyházi Brage Suzanne 
Published: October 2020

AbstractCurrent treatment modalities for disseminated cutaneous malignant melanoma (CMM) improve survival, however disease progression commonly ensues. In a previous study we identified afatinib and crizotinib in combination as a novel potential therapy for CMM independent of BRAF/NRAS mutation status. Herein, we elucidate the underlying mechanisms of the combination treatment effect to find biomarkers and novel targets for development of therapy that may provide clinical benefit by proteomic analysis of CMM cell lines and xenografts using mass spectrometry based analysis and reverse phase protein array. Identified candidates were validated using immunoblotting or immunofluorescence. Our analysis revealed that mTOR/Insulin signaling pathways were significantly decreased by the afatinib and crizotinib combination treatment. Both in vitro and in vivo analyses showed that the combination treatment downregulated pRPS6KB1 and pRPS6, downstream of mTOR signaling, and IRS-1 in the insulin signaling pathway, specifically ablating IRS-1 nuclear signal. Silencing of RPS6 and IRS-1 alone had a similar effect on cell death, which was further induced when IRS-1 and RPS6 were concomitantly silenced in the CMM cell lines. Silencing of IRS-1 and RPS6 resulted in reduced sensitivity towards combination treatment. Additionally, we found that IRS-1 and RPS6KB1 expression levels were increased in advanced stages of CMM clinical samples. We could demonstrate that induced resistance towards combination treatment was reversible by a drug holiday. CD171/L1CAM, mTOR and PI3K-p85 were induced in the combination resistant cells whereas AXL and EPHA2, previously identified mediators of resistance to MAPK inhibitor therapy in CMM were downregulated. We also found that CD171/L1CAM and mTOR were increased at progression in tumor biopsies from two matched cases of patients receiving targeted therapy with BRAFi. Overall, these findings provide insights into the molecular mechanisms behind the afatinib and crizotinib combination treatment effect and leverages a platform for discovering novel biomarkers and therapy regimes for CMM treatment.
Downregulation of PUMA underlies resistance to FGFR1 inhibitors in the stem cell leukemia/lymphoma syndrome
Authors: Liu Yun , Cai Baohuan , Chong Yating , Zhang Hualei , Kemp Chesley-Anne , Lu Sumin , Chang Chang-Sheng , Ren Mingqiang , Cowell John K. , Hu Tianxiang 
Published: October 2020

AbstractResistance to molecular therapies frequently occur due to genetic changes affecting the targeted pathway. In myeloid and lymphoid leukemias/lymphomas resulting from constitutive activation of FGFR1 kinases, resistance has been shown to be due either to mutations in FGFR1 or deletions of PTEN. RNA-Seq analysis of the resistant clones demonstrates expression changes in cell death pathways centering on the p53 upregulated modulator of apoptosis (Puma) protein. Treatment with different tyrosine kinase inhibitors (TKIs) revealed that, in both FGFR1 mutation and Pten deletion-mediated resistance, sustained Akt activation in resistant cells leads to compromised Puma activation, resulting in suppression of TKI-induced apoptosis. This suppression of Puma is achieved as a result of sequestration of inactivated p-Foxo3a in the cytoplasm. CRISPR/Cas9 mediated knockout of Puma in leukemic cells led to an increased drug resistance in the knockout cells demonstrating a direct role in TKI resistance. Since Puma promotes cell death by targeting Bcl2, TKI-resistant cells showed high Bcl2 levels and targeting Bcl2 with Venetoclax (ABT199) led to increased apoptosis in these cells. In vivo treatment of mice xenografted with resistant cells using ABT199 suppressed leukemogenesis and led to prolonged survival. This in-depth survey of the underlying genetic mechanisms of resistance has identified a potential means of treating FGFR1-driven malignancies that are resistant to FGFR1 inhibitors.
MEKK3-MEK5-ERK5 signaling promotes mitochondrial degradation
Authors: Craig Jane E. , Miller Joseph N. , Rayavarapu Raju R. , Hong Zhenya , Bulut Gamze B. , Zhuang Wei , Sakurada Sadie Miki , Temirov Jamshid , Low Jonathan A. , Chen Taosheng , Pruett-Miller Shondra M. , Huang Lily Jun-shen , Potts Malia B. 
Published: October 2020

AbstractMitochondria are vital organelles that coordinate cellular energy homeostasis and have important roles in cell death. Therefore, the removal of damaged or excessive mitochondria is critical for maintaining proper cellular function. The PINK1-Parkin pathway removes acutely damaged mitochondria through a well-characterized mitophagy pathway, but basal mitochondrial turnover occurs via distinct and less well-understood mechanisms. Here we report that the MEKK3-MEK5-ERK5 kinase cascade is required for mitochondrial degradation in the absence of exogenous damage. We demonstrate that genetic or pharmacological inhibition of the MEKK3-MEK5-ERK5 pathway increases mitochondrial content by reducing lysosome-mediated degradation of mitochondria under basal conditions. We show that the MEKK3-MEK5-ERK5 pathway plays a selective role in basal mitochondrial degradation but is not required for non-selective bulk autophagy, damage-induced mitophagy, or restraint of mitochondrial biogenesis. This illuminates the MEKK3-MEK5-ERK5 pathway as a positive regulator of mitochondrial degradation that acts independently of exogenous mitochondrial stressors.
Contribution of GATA6 to homeostasis of the human upper pilosebaceous unit and acne pathogenesis
Authors: Oulès Bénédicte , Philippeos Christina , Segal Joe , Tihy Matthieu , Vietri Rudan Matteo , Cujba Ana-Maria , Grange Philippe A. , Quist Sven , Natsuga Ken , Deschamps Lydia , Dupin Nicolas , Donati Giacomo , Watt Fiona M. 
Published: October 2020

AbstractAlthough acne is the most common human inflammatory skin disease, its pathogenic mechanisms remain incompletely understood. Here we show that GATA6, which is expressed in the upper pilosebaceous unit of normal human skin, is down-regulated in acne. GATA6 controls keratinocyte proliferation and differentiation to prevent hyperkeratinisation of the infundibulum, which is the primary pathological event in acne. When overexpressed in immortalised human sebocytes, GATA6 triggers a junctional zone and sebaceous differentiation program whilst limiting lipid production and cell proliferation. It modulates the immunological repertoire of sebocytes, notably by upregulating PD-L1 and IL10. GATA6 expression contributes to the therapeutic effect of retinoic acid, the main treatment for acne. In a human sebaceous organoid model GATA6-mediated down-regulation of the infundibular differentiation program is mediated by induction of TGFβ signalling. We conclude that GATA6 is involved in regulation of the upper pilosebaceous unit and may be an actionable target in the treatment of acne.
Selective neuronal degeneration in MATR3 S85C knock-in mouse model of early-stage ALS
Authors: Kao Ching Serena , van Bruggen Rebekah , Kim Jihye Rachel , Chen Xiao Xiao Lily , Chan Cadia , Lee Jooyun , Cho Woo In , Zhao Melody , Arndt Claudia , Maksimovic Katarina , Khan Mashiat , Tan Qiumin , Wilson Michael D. , Park Jeehye 
Published: October 2020

AbstractA missense mutation, S85C, in the MATR3 gene is a genetic cause for amyotrophic lateral sclerosis (ALS). It is unclear how the S85C mutation affects MATR3 function and contributes to disease. Here, we develop a mouse model that harbors the S85C mutation in the endogenous Matr3 locus using the CRISPR/Cas9 system. MATR3 S85C knock-in mice recapitulate behavioral and neuropathological features of early-stage ALS including motor impairment, muscle atrophy, neuromuscular junction defects, Purkinje cell degeneration and neuroinflammation in the cerebellum and spinal cord. Our neuropathology data reveals a loss of MATR3 S85C protein in the cell bodies of Purkinje cells and motor neurons, suggesting that a decrease in functional MATR3 levels or loss of MATR3 function contributes to neuronal defects. Our findings demonstrate that the MATR3 S85C mouse model mimics aspects of early-stage ALS and would be a promising tool for future basic and preclinical research.
Altered G1 signaling order and commitment point in cells proliferating without CDK4/6 activity
Authors: Liu Chad , Konagaya Yumi , Chung Mingyu , Daigh Leighton H. , Fan Yilin , Yang Hee Won , Terai Kenta , Matsuda Michiyuki , Meyer Tobias 
Published: October 2020

AbstractCell-cycle entry relies on an orderly progression of signaling events. To start, cells first activate the kinase cyclin D-CDK4/6, which leads to eventual inactivation of the retinoblastoma protein Rb. Hours later, cells inactivate APC/CCDH1 and cross the final commitment point. However, many cells with genetically deleted cyclin Ds, which activate and confer specificity to CDK4/6, can compensate and proliferate. Despite its importance in cancer, how this entry mechanism operates remains poorly characterized, and whether cells use this path under normal conditions remains unknown. Here, using single-cell microscopy, we demonstrate that cells with acutely inhibited CDK4/6 enter the cell cycle with a slowed and fluctuating cyclin E-CDK2 activity increase. Surprisingly, with low CDK4/6 activity, the order of APC/CCDH1 and Rb inactivation is reversed in both cell lines and wild-type mice. Finally, we show that as a consequence of this signaling inversion, Rb inactivation replaces APC/CCDH1 inactivation as the point of no return. Together, we elucidate the molecular steps that enable cell-cycle entry without CDK4/6 activity. Our findings not only have implications in cancer resistance, but also reveal temporal plasticity underlying the G1 regulatory circuit.
CHIP phosphorylation by protein kinase G enhances protein quality control and attenuates cardiac ischemic injury
Authors: Ranek Mark J. , Oeing Christian , Sanchez-Hodge Rebekah , Kokkonen-Simon Kristen M. , Dillard Danielle , Aslam M. Imran , Rainer Peter P. , Mishra Sumita , Dunkerly-Eyring Brittany , Holewinski Ronald J. , Virus Cornelia , Zhang Huaqun , Mannion Matthew M. , Agrawal Vineet , Hahn Virginia , Lee Dong I. , Sasaki Masayuki , Van Eyk Jennifer E. , Willis Monte S. , Page Richard C. , Schisler Jonathan C. , Kass David A. 
Published: October 2020

AbstractProteotoxicity from insufficient clearance of misfolded/damaged proteins underlies many diseases. Carboxyl terminus of Hsc70-interacting protein (CHIP) is an important regulator of proteostasis in many cells, having E3-ligase and chaperone functions and often directing damaged proteins towards proteasome recycling. While enhancing CHIP functionality has broad therapeutic potential, prior efforts have all relied on genetic upregulation. Here we report that CHIP-mediated protein turnover is markedly post-translationally enhanced by direct protein kinase G (PKG) phosphorylation at S20 (mouse, S19 human). This increases CHIP binding affinity to Hsc70, CHIP protein half-life, and consequent clearance of stress-induced ubiquitinated-insoluble proteins. PKG-mediated CHIP-pS20 or expressing CHIP-S20E (phosphomimetic) reduces ischemic proteo- and cytotoxicity, whereas a phospho-silenced CHIP-S20A amplifies both. In vivo, depressing PKG activity lowers CHIP-S20 phosphorylation and protein, exacerbating proteotoxicity and heart dysfunction after ischemic injury. CHIP-S20E knock-in mice better clear ubiquitinated proteins and are cardio-protected. PKG activation provides post-translational enhancement of protein quality control via CHIP.
Large array of Schrödinger cat states facilitated by an optical waveguide
Authors: Leong Wui Seng , Xin Mingjie , Chen Zilong , Chai Shijie , Wang Yu , Lan Shau-Yu 
Published: October 2020

AbstractQuantum engineering using photonic structures offer new capabilities for atom-photon interactions for quantum optics and atomic physics, which could eventually lead to integrated quantum devices. Despite the rapid progress in the variety of structures, coherent excitation of the motional states of atoms in a photonic waveguide using guided modes has yet to be demonstrated. Here, we use the waveguide mode of a hollow-core photonic crystal fibre to manipulate the mechanical Fock states of single atoms in a harmonic potential inside the fibre. We create a large array of Schrödinger cat states, a quintessential feature of quantum physics and a key element in quantum information processing and metrology, of approximately 15000 atoms along the fibre by entangling the electronic state with the coherent harmonic oscillator state of each individual atom. Our results provide a useful step for quantum information and simulation with a wide range of photonic waveguide systems.
Siah2 integrates mitogenic and extracellular matrix signals linking neuronal progenitor ciliogenesis with germinal zone occupancy
Authors: Ong Taren , Trivedi Niraj , Wakefield Randall , Frase Sharon , Solecki David J. 
Published: October 2020

AbstractEvidence is lacking as to how developing neurons integrate mitogenic signals with microenvironment cues to control proliferation and differentiation. We determine that the Siah2 E3 ubiquitin ligase functions in a coincidence detection circuit linking responses to the Shh mitogen and the extracellular matrix to control cerebellar granule neurons (CGN) GZ occupancy. We show that Shh signaling maintains Siah2 expression in CGN progenitors (GNPs) in a Ras/Mapk-dependent manner. Siah2 supports ciliogenesis in a feed-forward fashion by restraining cilium disassembly. Efforts to identify sources of the Ras/Mapk signaling led us to discover that GNPs respond to laminin, but not vitronectin, in the GZ microenvironment via integrin β1 receptors, which engages the Ras/Mapk cascade with Shh, and that this niche interaction is essential for promoting GNP ciliogenesis. As GNPs leave the GZ, differentiation is driven by changing extracellular cues that diminish Siah2-activity leading to primary cilia shortening and attenuation of the mitogenic response.
Birefringent Fourier filtering for single molecule coordinate and height super-resolution imaging with dithering and orientation
Authors: Curcio Valentina , Alemán-Castañeda Luis A. , Brown Thomas G. , Brasselet Sophie , Alonso Miguel A. 
Published: October 2020

AbstractSuper-resolution imaging based on single molecule localization allows accessing nanometric-scale information in biological samples with high precision. However, complete measurements including molecule orientation are still challenging. Orientation is intrinsically coupled to position in microscopy imaging, and molecular wobbling during the image integration time can bias orientation measurements. Providing 3D molecular orientation and orientational fluctuations would offer new ways to assess the degree of alignment of protein structures, which cannot be monitored by pure localization. Here we demonstrate that by adding polarization control to phase control in the Fourier plane of the imaging path, all parameters can be determined unambiguously from single molecules: 3D spatial position, 3D orientation and wobbling or dithering angle. The method, applied to fluorescent labels attached to single actin filaments, provides precisions within tens of nanometers in position and few degrees in orientation.