bluuebunny/crossref_metadata_2025_split huggingface dataset:
On the Choice and Implications of Rheologies That Maintain Kinematic and Dynamic Consistency Over the Entire Earthquake Cycle
Authors: Mallick Rishav , Lambert Valère , Meade Brendan 
Published: September 2022

AbstractViscoelastic processes in the upper mantle redistribute seismically generated stresses and modulate crustal deformation throughout the earthquake cycle. Geodetic observations of these motions at the surface of the crust‐mantle system offer the possibility of constraining the rheology of the upper mantle. Parsimonious representations of viscoelastically modulated deformation through the aseismic phase of the earthquake cycle should simultaneously explain geodetic observations of (a) rapid postseismic deformation, (b) late in the earthquake cycle near‐fault strain localization. To understand how rheological formulations affect kinematics, we compare predictions from time‐dependent forward models of deformation over the entire earthquake cycle for an idealized vertical strike‐slip fault in a homogeneous elastic crust underlain by a homogeneous viscoelastic upper‐mantle. We explore three different rheologies as inferred from laboratory experiments: (a) linear Maxwell, (b) linear Burgers, (c) power‐law. The linear Burgers and power‐law rheologies are consistent with fast and slow deformation phenomenology over the entire earthquake cycle, while the single‐layer linear Maxwell model is not. The kinematic similarity of linear Burgers and power‐law models suggests that geodetic observations alone may be insufficient to distinguish between them, but indicate that one may serve as an effective proxy for the other. However, the power‐law rheology model displays a postseismic response that is non‐linearly dependent on earthquake magnitude, which may offer a partial explanation for observations of limited postseismic deformation near some magnitude 6.5–7.0 earthquakes. We discuss the role of mechanical coupling between frictional slip and viscous creep in controlling the time‐dependence of regional stress transfer following large earthquakes and how this may affect the seismic hazard and risk to communities living close to fault networks.
Analysis of the Vibration Modes of Impact Geoplates and Implications for Bedload Flux and Grain Size Measurements
Authors: Portogallo M. , Simoni S. , Vignoli G. , Bertoldi W. 
Published: September 2022

AbstractSeismic geophones have been frequently used in combination with metal plates to indirectly estimate bedload flux in gravel bed mountain rivers. This indirect method has been calibrated with direct measurements in several conditions and proved effective to provide relevant information on spatial and temporal scales otherwise impossible to explore. Notwithstanding, a detailed description of the vibration modes of the plate is still lacking, limiting the possibility to interpret the signal. Here, we report on two sets of experiments where we explored the geoplate response in terms of frequency and amplitude of different vibrational modes. A first set of dry experiments was designed to investigate the variability of the signal as a function of the impact location on the plate. A second set reproduced standard flow conditions, with single pebbles transported by the flow. Results highlighted the occurrence of two main vibration modes, with a first rapid phase (about 5 ms) characterized by higher frequencies, and a second longer and more stable phase of vibration with a frequency in the range of 300–400 Hz. The signal of single impacts showed a good correlation with pebble mass, with only the number of impacts on the plate depending on the flow conditions. The evaluation of the grain size is a challenge given the variability of the signal generated by similar impacts. We propose a filtering strategy to improve grain size estimation. Our analysis shows that a more detailed understanding of the vibrational modes helps identifying best practices for an improved signal acquisition and elaboration.
Impact of Density Gradients on the Secondary Flow Structure of a River Confluence
Authors: Duguay J. , Biron P. M. , Lacey J. 
Published: September 2022

AbstractA small gradient in the densities (Δρ) of two rivers in Canada was recently shown to develop coherent streamwise orientated vortices (SOVs) in their confluence. Here we use eddy‐resolved numerical modeling to examine how the magnitude and direction of Δρ affect these secondary flow structures. At equal density, lone anticlockwise SOVs are predicted near the surface, a possibility supported herein by recent aerial observations of such SOVs at the confluence. When a Δρ is considered, a front from the denser channel always slides underneath the lighter channel independent of whether the dense front pushes into the fast (Coaticook) or slow (Massawippi) tributary. When the fast Coaticook is denser, coherent clockwise rotating SOVs tend to form. However, when the slow Massawippi is denser, interfacial instabilities are generated as the fast flow of the Coaticook shears overtop the dense front. Thus, the tributary's velocity opposing the dense front's propagation modifies secondary flow characteristics. Importantly, both these cases would have the same densimetric Froude number (FD) if defined using an average velocity of the confluence (e.g., that of the downstream channel), yet this single FD value cannot account for the differences observed between both. This ambiguity inherent to current conventions for calculating FD places into question its use as an adequate predictor of density‐driven secondary flow at confluences.
Metabolic improvement and liver regeneration by inhibiting CXXC5 function for non-alcoholic steatohepatitis treatment
Authors: Seo Seol Hwa , Kim Eunhwan , Yoon Minguen , Lee Soung-Hoon , Park Byung-Hyun , Choi Kang-Yell 
Published: September 2022

AbstractNon-alcoholic steatohepatitis (NASH) is a chronic liver disease that results from multiple metabolic disorders. Considering the complexity of the pathogenesis, the identification of a factor mediating the multiple pathogenic phenotypes of NASH will be important for treatment. In this study, we found that CXXC5, a negative feedback regulator of the Wnt/β-catenin pathway, was overexpressed with suppression of Wnt/β-catenin signaling and its target genes involved in hepatic metabolism in obese-NASH patients. Cxxc5−/− mice were found to be resistant to NASH pathogenesis with metabolic improvements. KY19334, a small molecule that activates the Wnt/β-catenin pathway via interference of the CXXC5-Dvl interaction, reversed the overall pathogenic features of NASH as Cxxc5−/− mice. The improvement in NASH by KY19334 is attributed to its regenerative effects through restorative activation of the suppressed Wnt/β-catenin signaling. Overall, the pronounced metabolic improvements with the stimulation of liver regeneration by interfering with the CXXC5-Dvl interaction provide a therapeutic approach for NASH.
Leveraging interindividual variability of regulatory activity for refining genetic regulation of gene expression in schizophrenia
Authors: Alver Maris , Lykoskoufis Nikolaos , Ramisch Anna , Dermitzakis Emmanouil T. , Ongen Halit 
Published: September 2022

AbstractSchizophrenia is a polygenic psychiatric disorder with limited understanding about the mechanistic changes in gene expression regulation. To elucidate on this, we integrate interindividual variability of regulatory activity (ChIP-sequencing for H3K27ac histone mark) with gene expression and genotype data captured from the prefrontal cortex of 272 cases and controls. By measuring interindividual correlation among proximal chromatin peaks, we show that regulatory element activity is structured into 10,936 and 10,376 cis-regulatory domains in cases and controls, respectively. The schizophrenia-specific cis-regulatory domains are enriched for fetal-specific (p = 0.0014, OR = 1.52) and depleted of adult-specific regulatory activity (p = 3.04 × 10−50, OR = 0.57) and are enriched for SCZ heritability (p = 0.001). By studying the interplay among genetic variants, gene expression, and cis-regulatory domains, we ascertain that changes in coordinated regulatory activity tag alterations in gene expression levels (p = 3.43 × 10−5, OR = 1.65), unveil case-specific QTL effects, and identify regulatory machinery changes for genes affecting synaptic function and dendritic spine morphology in schizophrenia. Altogether, we show that accounting for coordinated regulatory activity provides a novel mechanistic approach to reduce the search space for unveiling genetically perturbed regulation of gene expression in schizophrenia.
Difficulties capturing co-occurring traumatic brain injury among people with traumatic spinal cord injury: a population-based study
Authors: Snell Deborah L. , Johns Julianne , Dunn Jennifer A. , Nunnerley Joanne L. , Singhal Balraj 
Published: September 2022

Abstract

Study design
This is a population-based prospective cohort study.

Objectives
Traumatic brain injury (TBI) is common among people with traumatic spinal cord injury (TSCI), but rates vary across studies associated with variable approaches to diagnosis. We aimed to determine if a published diagnostic algorithm could be consistently applied to capture co-occurring TBI among persons sustaining TSCI.

Setting
One of two spinal centres in New Zealand (NZ), the Burwood Spinal Unit (BSU) captures approximately 45% of NZ TSCI admissions.

Methods
Adults (age 16+) with TSCI admitted to the BSU between 1 January 2021 and 31 August 2021 (n = 51) were included. Clinical notes were audited prospectively to identify co-occurring TBI.

Results
We identified co-occurring TBI in 39% of TSCI cases with a small number of additional suspected TBI cases where TBI could not be confidently ruled in or out. Including all TBI cases, suspected or otherwise resulted in up to 55% of the sample having sustained co-occurring TBI. There were difficulties applying the published algorithm, associated with inconsistent documentation of TBI indicators from acute to rehabilitation contexts.

Conclusions
In this study, the feasibility of a TBI diagnostic algorithm for the TSCI population was low. Alternative approaches to screening for TBI among people sustaining TSCI are needed. Greater consistency in documenting TBI across the continuum of care will ensure TBI if present, is included in treatment planning.
Knock-out of 5-lipoxygenase in overexpressing tumor cells—consequences on gene expression and cellular function
Authors: Weisser Hannah , Göbel Tamara , Melissa Krishnathas G. , Kreiß Marius , Angioni Carlo , Sürün Duran , Thomas Dominique , Schmid Tobias , Häfner Ann-Kathrin , Kahnt Astrid S. 
Published: September 2022

Abstract5-Lipoxygenase (5-LO), the central enzyme in the biosynthesis of leukotrienes, is frequently expressed in human solid malignancies even though the enzyme is not present in the corresponding healthy tissues. There is little knowledge on the consequences of this expression for the tumor cells regarding gene expression and cellular function. We established a knockout (KO) of 5-LO in different cancer cell lines (HCT-116, HT-29, U-2 OS) and studied the consequences on global gene expression using next generation sequencing. Furthermore, cell viability, proliferation, migration and multicellular tumor spheroid (MCTS) formation were studied in these cells. Our results show that 5-LO influences the gene expression and cancer cell function in a cell type-dependent manner. The enzyme affected genes involved in cell adhesion, extracellular matrix formation, G protein signaling and cytoskeleton organization. Furthermore, absence of 5-LO elevated TGFβ2expression in HCT-116 cells while MCP-1, fractalkine and platelet-derived growth factor expression was attenuated in U-2 OS cells suggesting that tumor cell-derived 5-LO shapes the tumor microenvironment. In line with the gene expression data, KO of 5-LO had an impact on cell proliferation, motility and MCTS formation. Interestingly, pharmacological inhibition of 5-LO only partly mimicked the KO suggesting that also noncanonical functions are involved.
Structural impact of arrested foveal development in children born extremely preterm without ROP at 6.5 years of age
Authors: Venkataraman Abinaya Priya , Popovic Zoran , Hellgren Kerstin , Sjöstrand Johan , Nilsson Maria 
Published: September 2022

Abstract
Objectives
To characterize changes of foveal topography and microstructure of persisting foveal immaturity at 6.5 years of age in children born extremely preterm without retinopathy of prematurity (EPT-NoROP).

Methods
Images from previous optical coherence tomography examinations of 37 EPT-NoROP and 92 control eyes were selected from a regional cohort of the EXPRESS (Extremely Preterm Infants in Sweden) study. Thickness of ganglion cell + inner plexiform layer (GCL+), outer nuclear layer (ONL), retinal thickness (RT) at the foveal centre (FC), foveal depth (FD) and RT at the foveal rim were evaluated.

Results
Layer thickness of GCL+, ONL and RT was increased at FC in the EPT-NoROP group. More than two-thirds had thickness values above the control limit (control mean +2 SD) at FC (GCL + 68%, ONL 76%, and RT 68%), and 50% had reduced FD compared to controls. All parameters showed a high correlation within the EPT-NoROP group, whereas no or weaker correlation was seen in control eyes. The EPT-NoROP sub-groups, divided based on the control limit, did not differ in terms of associated factors such as gestational age, birth weight, visual acuity, and refraction.

Conclusions
Extreme prematurity without impact of ROP is associated with increased GCL + , ONL, and RT thickness at FC as well as reduced FD compared to full-term controls at age 6.5. This indicates that prematurity per se may have a profound effect on foveal anatomical maturation during the first months after birth. Our results suggest RT at FC to be a simple and useful measure of foveal anatomical immaturity.
Electrostatic and steric effects underlie acetylation-induced changes in ubiquitin structure and function
Authors: Kienle Simon Maria , Schneider Tobias , Stuber Katrin , Globisch Christoph , Jansen Jasmin , Stengel Florian , Peter Christine , Marx Andreas , Kovermann Michael , Scheffner Martin 
Published: September 2022

AbstractCovalent attachment of ubiquitin (Ub) to proteins is a highly versatile posttranslational modification. Moreover, Ub is not only a modifier but itself is modified by phosphorylation and lysine acetylation. However, the functional consequences of Ub acetylation are poorly understood. By generation and comprehensive characterization of all seven possible mono-acetylated Ub variants, we show that each acetylation site has a particular impact on Ub structure. This is reflected in selective usage of the acetylated variants by different E3 ligases and overlapping but distinct interactomes, linking different acetylated variants to different cellular pathways. Notably, not only electrostatic but also steric effects contribute to acetylation-induced changes in Ub structure and, thus, function. Finally, we provide evidence that p300 acts as a position-specific Ub acetyltransferase and HDAC6 as a general Ub deacetylase. Our findings provide intimate insights into the structural and functional consequences of Ub acetylation and highlight the general importance of Ub acetylation.
Conserved features of TERT promoter duplications reveal an activation mechanism that mimics hotspot mutations in cancer
Authors: Barger Carter J. , Suwala Abigail K. , Soczek Katarzyna M. , Wang Albert S. , Kim Min Y. , Hong Chibo , Doudna Jennifer A. , Chang Susan M. , Phillips Joanna J. , Solomon David A. , Costello Joseph F. 
Published: September 2022

AbstractMutations in the TERT promoter represent the genetic underpinnings of tumor cell immortality. Beyond the two most common point mutations, which selectively recruit the ETS factor GABP to activate TERT, the significance of other variants is unknown. In seven cancer types, we identify duplications of wildtype sequence within the core promoter region of TERT that have strikingly similar features including an ETS motif, the duplication length and insertion site. The duplications recruit a GABP tetramer by virtue of the native ETS motif and its precisely spaced duplicated counterpart, activate the promoter and are clonal in a TERT expressing multifocal glioblastoma. We conclude that recurrent TERT promoter duplications are functionally and mechanistically equivalent to the hotspot mutations that confer tumor cell immortality. The shared mechanism of these divergent somatic genetic alterations suggests a strong selective pressure for recruitment of the GABP tetramer to activate TERT.
A multi-adenylate cyclase regulator at the flagellar tip controls African trypanosome transmission
Authors: Bachmaier Sabine , Giacomelli Giacomo , Calvo-Alvarez Estefanía , Vieira Larissa Rezende , Van Den Abbeele Jan , Aristodemou Aris , Lorentzen Esben , Gould Matt K. , Brennand Ana , Dupuy Jean-William , Forné Ignasi , Imhof Axel , Bramkamp Marc , Salmon Didier , Rotureau Brice , Boshart Michael 
Published: September 2022

AbstractSignaling from ciliary microdomains controls developmental processes in metazoans. Trypanosome transmission requires development and migration in the tsetse vector alimentary tract. Flagellar cAMP signaling has been linked to parasite social motility (SoMo) in vitro, yet uncovering control of directed migration in fly organs is challenging. Here we show that the composition of an adenylate cyclase (AC) complex in the flagellar tip microdomain is essential for tsetse salivary gland (SG) colonization and SoMo. Cyclic AMP response protein 3 (CARP3) binds and regulates multiple AC isoforms. CARP3 tip localization depends on the cytoskeletal protein FLAM8. Re-localization of CARP3 away from the tip microdomain is sufficient to abolish SoMo and fly SG colonization. Since intrinsic development is normal incarp3andflam8knock-out parasites, AC complex-mediated tip signaling specifically controls parasite migration and thereby transmission. Participation of several developmentally regulated receptor-type AC isoforms may indicate the complexity of the in vivo signals perceived.
Structures reveal a key mechanism of WAVE regulatory complex activation by Rac1 GTPase
Authors: Ding Bojian , Yang Sheng , Schaks Matthias , Liu Yijun , Brown Abbigale J. , Rottner Klemens , Chowdhury Saikat , Chen Baoyu 
Published: September 2022

AbstractThe Rho-family GTPase Rac1 activates the WAVE regulatory complex (WRC) to drive Arp2/3 complex-mediated actin polymerization in many essential processes. Rac1 binds to WRC at two distinct sites—the A and D sites. Precisely how Rac1 binds and how the binding triggers WRC activation remain unknown. Here we report WRC structures by itself, and when bound to single or double Rac1 molecules, at ~3 Å resolutions by cryogenic-electron microscopy. The structures reveal that Rac1 binds to the two sites by distinct mechanisms, and binding to the A site, but not the D site, drives WRC activation. Activation involves a series of unique conformational changes leading to the release of sequestered WCA (WH2-central-acidic) polypeptide, which stimulates the Arp2/3 complex to polymerize actin. Together with biochemical and cellular analyses, the structures provide a novel mechanistic understanding of how the Rac1-WRC-Arp2/3-actin signaling axis is regulated in diverse biological processes and diseases.
Interactions between the cortical midline structures and sensorimotor network track maladaptive self-beliefs in clinical high risk for psychosis
Authors: Cowan Henry R. , Damme Katherine S. F. , Mittal Vijay A. 
Published: September 2022

AbstractIndividuals at clinical high risk for psychosis (CHR) report a maladaptive self-concept—with more negative and less positive self-beliefs—linked to clinical symptoms and functional impairment. Alterations have also been reported in brain networks associated with intrinsic (cortical midline structures, CMS) and extrinsic (sensorimotor network, SMN) self-processing. Theoretical accounts of multiple levels of self-experience in schizophrenia suggest that interactions between these networks would be relevant for self-beliefs. This study tested whether self-beliefs related to resting-state functional connectivity within and between the CMS and SMN. Participants were 56 individuals meeting CHR criteria and 59 matched healthy community participants (HC). Pearson correlations examined potential mediators and outcomes. The CHR group reported more negative and less positive self-beliefs. Greater resting-state functional connectivity between the posterior CMS (posterior cingulate cortex) and the SMN was associated with less positive self-beliefs in CHR, but more positive self-beliefs in HC. Attenuated negative symptoms and poorer social functioning were associated with CMS-SMN connectivity (trend level after FDR-correction) and self-beliefs. Reduced connectivity between the left and right PCC was associated with lower positive self-beliefs in CHR, although this effect was specific to very low levels of positive self-beliefs. Left-right PCC connectivity did not correlate with outcomes. Dynamic interactions between intrinsic and extrinsic self-processing supported positive self-beliefs in typically developing youth while undermining positive self-beliefs in CHR youth. Implications are discussed for basic self-fragmentation, narrative self-related metacognition, and global belief updating. Interventions for self-processing may be beneficial in the CHR syndrome.
Incidence of and risk factors for severe neutropenia during treatment with the modified FOLFIRINOX therapy in patients with advanced pancreatic cancer
Authors: Irisawa Ai , Takeno Misaki , Watanabe Kazuo , Takahashi Hideaki , Mitsunaga Shuichi , Ikeda Masafumi 
Published: September 2022

AbstractAlthough FOLFIRINOX (l-Leucovorin/5-FU/Irinotecan/Oxaliplatin) is established as one of the standard therapies for patients with metastatic pancreatic cancer, the modified FOLFIRINOX (mFOLFIRINOX) is often used in clinical practice to reduce the incidence of toxicities. Febrile neutropenia (FN) and severe neutropenia during FOLFIRINOX are especially frequently observed in Japanese patients. In this study, we evaluated the incidence of FN and severe neutropenia, and explored the risk factors for severe neutropenia in patients receiving treatment with mFOLFIRINOX. The data of patients who had received mFOLFIRINOX between December 2013 and December 2014 at the National Cancer Center Hospital East were reviewed retrospectively. We graded the neutropenia severity and defined ≥ Grade 3 neutropenia as severe neutropenia. Univariate and multivariate analysis were undertaken to evaluate the associations with risk of development of severe neutropenia. A total of 122 patients were enrolled in this study. Sixty two patients (51%) and 10 patients (8%) developed severe neutropenia and FN, respectively. Multivariate analysis identified a low baseline white blood cell count (odds ratio [OR], 14.50; 95% confidence interval (CI), 3.27–111.14; p = 0.002) and presence of heterozygosity for UGT1A1*28 or UGT1A1*6 polymorphism (OR, 2.84; 95% CI, 1.18–7.17; p = 0.023) as independent risk factors for severe neutropenia. The incidences of severe neutropenia and FN in patients receiving mFOLFIRINOX in our clinical practice were comparable to previous reports. The risk factors for severe neutropenia in patients receiving mFOLFIRINOX were a low baseline white blood cell count and presence of heterozygosity for UGT1A1*28 or UGT1A1*6 polymorphism.