bluuebunny/crossref_metadata_2025_split huggingface dataset:
Coupling Between Lithosphere Removal and Mantle Flow in the Central Andes
Authors: Wang Huilin , Currie Claire A. , DeCelles Peter G. 
Published: August 2021

AbstractThe central Andes is part of a Cordilleran orogen formed through continent‐ocean convergence. In contrast to the thickened crust, the mantle lithosphere below much of the orogen is anomalously thin. Additionally, the surface is characterized by widespread backarc magmatism and transient ∼100‐km‐wide basins that developed the over last 30 million years, with basins located systematically seaward of major backarc ignimbrite centers and basin formation predating the late Miocene magma/ignimbrite flare‐up. Using numerical models, we propose a novel mechanism whereby lithosphere removal is coupled with mantle flow. First, a small area of high‐density eclogitized lower crust initiates a gravitational instability, causing a localized basin at the surface that subsides and then uplifts. Foundering crust and adjacent lithosphere are entrained by subduction‐induced mantle flow, driving regional lithosphere removal and magmatism. The models demonstrate that mantle flow can amplify a local lithosphere instability to orogen‐wide lithosphere removal, rapidly eliminating accumulated mass in the orogen.
Mode of Precipitation Variability Generated by Coupling of ENSO With Seasonal Cycle in the Tropical Pacific
Authors: Fukuda Yoshihiro , Watanabe Masahiro , Jin Fei‐Fei 
Published: August 2021

AbstractTropical precipitation anomalies show very different patterns over the central‐eastern equatorial Pacific between the developing and decay phases of extreme El Niño despite similar patterns of sea surface temperature (SST) anomalies. Using observational data and atmospheric simulations for 1979–2018, we identified a meridional dipole mode of tropical precipitation variability, called the Pacific precipitation dipole mode (PPDM), which is critical for seasonally varying rainfall patterns related to extreme El Niño. We examined the mechanism of PPDM using a numerical model and found that the seasonal shift of the warm SST band in the eastern equatorial Pacific, when coupled with extreme SST anomalies, causes phase reversal of the PPDM. The PPDM can be regarded as a different manifestation of the El Niño/Southern Oscillation combination mode, as revealed by the surface wind anomalies, which also explains the distinct impact of extreme El Niño events over East Asia.
Global Flash Drought Monitoring Using Surface Soil Moisture
Authors: Sehgal Vinit , Gaur Nandita , Mohanty Binayak P. 
Published: August 2021

AbstractAbrupt onset and swift intensification characterize flash droughts. Global surface soil moisture (θRS) from NASA's Soil Moisture Active Passive (SMAP) satellite can facilitate a near‐real‐time assessment of emerging flash droughts at a 36‐km footprint. However, a robust flash drought monitoring using θRS must account for the (a) short observation record of SMAP, (b) nonlinear geophysical controls over θRS dynamics, and (c) emergent meteorological drivers of flash droughts. We propose a new method for near‐real‐time characterization of droughts using Soil Moisture Stress (SMS, drought stress) and Relative Rate of Drydown (RRD, drought stress intensification rate)—developed using SMAP θRS (March 2015–May 2021), footprint‐scale seasonal soil water retention parameters and land‐atmospheric coupling strength. SMS and RRD are nonlinearly combined to develop Flash Drought Stress Index (FDSI) to characterize emerging flash droughts (FDSI ≥ 0.71 for moderate to high RRD and SMS). Globally, FDSI shows a high correlation with concurrent meteorological anomalies. A mechanistic evaluation of flash droughts is presented for the Northern Great Plains, Central South Africa, and Eastern Australia using FDSI, SMS, and RRD. About 5.6% of the earth's landmass experienced flash droughts of varying intensity and duration during 2015–2021 (FDSI ≥ 0.71 for >30 consecutive days), majorly in global drylands. FDSI shows high skill in forecasting vegetation health with a lead of 0–2 weeks, with exceptions in irrigated croplands and mixed forests. With readily available parameters, low data latency, and no dependence on model simulations, we provide a robust tool for global near‐real‐time flash drought monitoring using SMAP.
Sustained intracellular calcium rise mediates neuronal mitophagy in models of autosomal dominant optic atrophy
Authors: Zaninello Marta , Palikaras Konstantinos , Sotiriou Aggeliki , Tavernarakis Nektarios , Scorrano Luca 
Published: August 2021

AbstractMitochondrial dysfunction and mitophagy are often hallmarks of neurodegenerative diseases such as autosomal dominant optic atrophy (ADOA) caused by mutations in the key mitochondrial dynamics protein optic atrophy 1 (Opa1). However, the second messengers linking mitochondrial dysfunction to initiation of mitophagy remain poorly characterized. Here, we show in mammalian and nematode neurons that Opa1 mutations trigger Ca2+-dependent mitophagy. Deletion or expression of mutated Opa1 in mouse retinal ganglion cells andCaenorhabditis elegansmotor neurons lead to mitochondrial dysfunction, increased cytosolic Ca2+levels, and decreased axonal mitochondrial density. Chelation of Ca2+restores mitochondrial density in neuronal processes, neuronal function, and viability. Mechanistically, sustained Ca2+levels activate calcineurin and AMPK, placed in the same genetic pathway regulating axonal mitochondrial density. Our data reveal that mitophagy in ADOA depends on Ca2+-calcineurin-AMPK signaling cascade.
Routinization of prenatal screening with the non-invasive prenatal test: pregnant women’s perspectives
Authors: van der Meij Karuna R. M. , Njio Annabel , Martin Linda , Gitsels-van der Wal Janneke T. , Bekker Mireille N. , van Vliet-Lachotzki Elsbeth H. , van der Ven A. Jeanine E. M. , Kater-Kuipers Adriana , Timmermans Danielle R. M. , Sistermans Erik A. , Galjaard Robert-Jan H. , Henneman Lidewij ,   the Dutch NIPT Consortium
Published: August 2021

AbstractDue to the favorable test characteristics of the non-invasive prenatal test (NIPT) in the screening of fetal aneuploidy, there has been a strong and growing demand for implementation. In the Netherlands, NIPT is offered within a governmentally supported screening program as a first-tier screening test for all pregnant women (TRIDENT-2 study). However, concerns have been raised that the test’s favorable characteristics might lead to uncritical use, also referred to as routinization. This study addresses women’s perspectives on prenatal screening with NIPT by evaluating three aspects related to routinization: informed choice, freedom to choose and (personal and societal) perspectives on Down syndrome. Nationwide, a questionnaire was completed by 751 pregnant women after receiving counseling for prenatal screening. Of the respondents, the majority (75.5%) made an informed choice for prenatal screening as measured by the multidimensional measure of informed choice (MMIC). Education level and religious affiliation were significant predictors of informed choice. The main reason to accept screening was “seeking reassurance” (25.5%), and the main reason to decline was “every child is welcome” (30.6%). The majority of respondents (87.7%) did not perceive societal pressure to test. Differences between test-acceptors and test-decliners in personal and societal perspectives on Down syndrome were found. Our study revealed high rates of informed decision-making and perceived freedom to choose regarding fetal aneuploidy screening, suggesting that there is little reason for concern about routinization of NIPT based on the perspectives of Dutch pregnant women. Our findings highlight the importance of responsible implementation of NIPT within a national screening program.
Neuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior
Authors: Blaze J. , Navickas A. , Phillips H. L. , Heissel S. , Plaza-Jennings A. , Miglani S. , Asgharian H. , Foo M. , Katanski C. D. , Watkins C. P. , Pennington Z. T. , Javidfar B. , Espeso-Gil S. , Rostandy B. , Alwaseem H. , Hahn C. G. , Molina H. , Cai D. J. , Pan T. , Yao W. D. , Goodarzi H. , Haghighi F. , Akbarian S. 
Published: August 2021

AbstractEpitranscriptomic mechanisms linking tRNA function and the brain proteome to cognition and complex behaviors are not well described. Here, we report bi-directional changes in depression-related behaviors after genetic disruption of neuronal tRNA cytosine methylation, including conditional ablation and transgene-derived overexpression of Nsun2 in the mouse prefrontal cortex (PFC). Neuronal Nsun2-deficiency was associated with a decrease in tRNA m5C levels, resulting in deficits in expression of 70% of tRNAGlyisodecoders. Altogether, 1488/5820 proteins changed upon neuronal Nsun2-deficiency, in conjunction with glycine codon-specific defects in translational efficiencies. Loss of Gly-rich proteins critical for glutamatergic neurotransmission was associated with impaired synaptic signaling at PFC pyramidal neurons and defective contextual fear memory. Changes in the neuronal translatome were also associated with a 146% increase in glycine biosynthesis. These findings highlight the methylation sensitivity of glycinergic tRNAs in the adult PFC. Furthermore, they link synaptic plasticity and complex behaviors to epitranscriptomic modifications of cognate tRNAs and the proteomic homeostasis associated with specific amino acids.
Metabolome and proteome analyses reveal transcriptional misregulation in glycolysis of engineered E. coli
Authors: Wang Chun-Ying , Lempp Martin , Farke Niklas , Donati Stefano , Glatter Timo , Link Hannes 
Published: August 2021

AbstractSynthetic metabolic pathways are a burden for engineered bacteria, but the underlying mechanisms often remain elusive. Here we show that the misregulated activity of the transcription factor Cra is responsible for the growth burden of glycerol overproducing E. coli. Glycerol production decreases the concentration of fructose-1,6-bisphoshate (FBP), which then activates Cra resulting in the downregulation of glycolytic enzymes and upregulation of gluconeogenesis enzymes. Because cells grow on glucose, the improper activation of gluconeogenesis and the concomitant inhibition of glycolysis likely impairs growth at higher induction of the glycerol pathway. We solve this misregulation by engineering a Cra-binding site in the promoter controlling the expression of the rate limiting enzyme of the glycerol pathway to maintain FBP levels sufficiently high. We show the broad applicability of this approach by engineering Cra-dependent regulation into a set of constitutive and inducible promoters, and use one of them to overproduce carotenoids in E. coli.
The conformational stability of pro-apoptotic BAX is dictated by discrete residues of the protein core
Authors: Bloch Noah B. , Wales Thomas E. , Prew Michelle S. , Levy Hannah R. , Engen John R. , Walensky Loren D. 
Published: August 2021

AbstractBAX is a pro-apoptotic member of the BCL-2 family, which regulates the balance between cellular life and death. During homeostasis, BAX predominantly resides in the cytosol as a latent monomer but, in response to stress, transforms into an oligomeric protein that permeabilizes the mitochondria, leading to apoptosis. Because renegade BAX activation poses a grave risk to the cell, the architecture of BAX must ensure monomeric stability yet enable conformational change upon stress signaling. The specific structural features that afford both stability and dynamic flexibility remain ill-defined and represent a critical control point of BAX regulation. We identify a nexus of interactions involving four residues of the BAX core α5 helix that are individually essential to maintaining the structure and latency of monomeric BAX and are collectively required for dimeric assembly. The dual yet distinct roles of these residues reveals the intricacy of BAX conformational regulation and opportunities for therapeutic modulation.
Genotoxic stress and viral infection induce transient expression of APOBEC3A and pro-inflammatory genes through two distinct pathways
Authors: Oh Sunwoo , Bournique Elodie , Bowen Danae , Jalili Pégah , Sanchez Ambrocio , Ward Ian , Dananberg Alexandra , Manjunath Lavanya , Tran Genevieve P. , Semler Bert L. , Maciejowski John , Seldin Marcus , Buisson Rémi 
Published: August 2021

AbstractAPOBEC3A is a cytidine deaminase driving mutagenesis in tumors. While APOBEC3A-induced mutations are common, APOBEC3A expression is rarely detected in cancer cells. This discrepancy suggests a tightly controlled process to regulate episodic APOBEC3A expression in tumors. In this study, we find that both viral infection and genotoxic stress transiently up-regulate APOBEC3A and pro-inflammatory genes using two distinct mechanisms. First, we demonstrate that STAT2 promotes APOBEC3A expression in response to foreign nucleic acid via a RIG-I, MAVS, IRF3, and IFN-mediated signaling pathway. Second, we show that DNA damage and DNA replication stress trigger a NF-κB (p65/IkBα)-dependent response to induce expression of APOBEC3A and other innate immune genes, independently of DNA or RNA sensing pattern recognition receptors and the IFN-signaling response. These results not only reveal the mechanisms by which tumors could episodically up-regulate APOBEC3A but also highlight an alternative route to stimulate the immune response after DNA damage independently of cGAS/STING or RIG-I/MAVS.
Potent antitumor activity of a glutamyltransferase-derived peptide via an activation of oncosis pathway
Authors: Fang Cheng , Li Wenhui , Yin Ruozhe , Zhu Donglie , Liu Xing , Wu Huihui , Wang Qingqiang , Wang Wenwen , Bai Quan , Chen Biliang , Yao Xuebiao , Chen Yong 
Published: August 2021

AbstractHepatocellular carcinoma (HCC) still presents poor prognosis with high mortality rate, despite of the improvement in the management. The challenge for precision treatment was due to the fact that little targeted therapeutics are available for HCC. Recent studies show that metabolic and circulating peptides serve as endogenous switches for correcting aberrant cellular plasticity. Here we explored the antitumor activity of low molecular components in human umbilical serum and identified a high abundance peptide VI-13 by peptidome analysis, which was recognized as the part of glutamyltransferase signal peptide. We modified VI-13 by inserting four arginines and obtained an analog peptide VI-17 to improve its solubility. Our analyses showed that the peptide VI-17 induced rapid context-dependent cell death, and exhibited a higher sensitivity on hepatoma cells, which is attenuated by polyethylene glycol but not necrotic inhibitors such as z-VAD-fmk or necrostatin-1. Morphologically, VI-17 induced cell swelling, blebbing and membrane rupture with release of cellular ATP and LDH into extracellular media, which is hallmark of oncotic process. Mechanistically, VI-17 induced cell membrane pore formation, degradation of α-tubulin via influx of calcium ion. These results indicated that the novel peptide VI-17 induced oncosis in HCC cells, which could serve as a promising lead for development of therapeutic intervention of HCC.
miR-141 mediates recovery from acute kidney injury
Authors: Newbury Lucy J. , Simpson Kate , Khalid Usman , John Imogen , de Rivera Lluís Bailach , Lu Yueh-An , Lopez-Anton Melisa , Watkins William J. , Jenkins Robert H. , Fraser Donald J. , Bowen Timothy 
Published: August 2021

AbstractAcute kidney injury (AKI) is a global clinical problem characterised by a sudden decline in renal function and mortality as high as 60%. Current AKI biomarkers have limited ability to classify disease progression and identify underlying pathological mechanisms. Here we hypothesised that alterations in urinary microRNA profiles could predict AKI recovery/nonrecovery after 90 days, and that injury-specific changes would signify microRNA mediators of AKI pathology. Comparison of urinary microRNA profiles from AKI patients with controls detected significant injury-specific increases in miR-21, miR-126 and miR-141 (p < 0.05) and decreases in miR-192 (p < 0.001) and miR-204 (p < 0.05). Expression of miR-141 increased in renal proximal tubular epithelial cells (PTECs) under oxidative stress in vitro and unilateral ischaemic reperfusion injury in vivo. Forced miR-141 expression in the presence of H2O2 increased PTEC death and decreased cell viability. Of nine messenger RNA targets with two or more miR-141 3’-untranslated region binding sites, we confirmed protein tyrosine phosphatase receptor type G (PTPRG) as a direct miR-141 target in PTECs. PTPRG-specific siRNA knockdown under oxidative stress increased PTEC death and decreased cell viability. In conclusion, we detected significant alterations in five urinary microRNAs following AKI, and identified proximal tubular cell PTPRG as a putative novel therapeutic target.
Expression of oncogenic HRAS in human Rh28 and RMS-YM rhabdomyosarcoma cells leads to oncogene-induced senescence
Authors: Li Jenny J. , Kovach Alexander R. , DeMonia Margaret , Slemmons Katherine K. , Oristian Kristianne M. , Chen Candy , Linardic Corinne M. 
Published: August 2021

AbstractRhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. The two predominant histologic variants of RMS, embryonal and alveolar rhabdomyosarcoma (eRMS and aRMS, respectively), carry very different prognoses. While eRMS is associated with an intermediate prognosis, the 5-year survival rate of aRMS is less than 30%. The RMS subtypes are also different at the molecular level—eRMS frequently has multiple genetic alterations, including mutations in RAS and TP53, whereas aRMS often has chromosomal translocations resulting in PAX3-FOXO1 or PAX7-FOXO1 fusions, but otherwise has a “quiet” genome. Interestingly, mutations in RAS are rarely found in aRMS. In this study, we explored the role of oncogenic RAS in aRMS. We found that while ectopic oncogenic HRAS expression was tolerated in the human RAS-driven eRMS cell line RD, it was detrimental to cell growth and proliferation in the human aRMS cell line Rh28. Growth inhibition was mediated by oncogene-induced senescence and associated with increased RB pathway activity and expression of the cyclin-dependent kinase inhibitors p16 and p21. Unexpectedly, the human eRMS cell line RMS-YM, a RAS wild-type eRMS cell line, also exhibited growth inhibition in response to oncogenic HRAS in a manner similar to aRMS Rh28 cells. This work suggests that oncogenic RAS is expressed in a context-dependent manner in RMS and may provide insight into the differential origins and therapeutic opportunities for RMS subtypes.
Donor genetic variants in interleukin-6 and interleukin-6 receptor associate with biopsy-proven rejection following kidney transplantation
Authors: Poppelaars Felix , Gaya da Costa Mariana , Eskandari Siawosh K. , Damman Jeffrey , Seelen Marc A. 
Published: August 2021

AbstractRejection after kidney transplantation remains an important cause of allograft failure that markedly impacts morbidity. Cytokines are a major player in rejection, and we, therefore, explored the impact of interleukin-6 (IL6) and IL-6 receptor (IL6R) gene polymorphisms on the occurrence of rejection after renal transplantation. We performed an observational cohort study analyzing both donor and recipient DNA in 1271 renal transplant‐pairs from the University Medical Center Groningen in The Netherlands and associated single nucleotide polymorphisms (SNPs) with biopsy-proven rejection after kidney transplantation. The C-allele of the IL6R SNP (Asp358Ala; rs2228145 A > C, formerly rs8192284) in donor kidneys conferred a reduced risk of rejection following renal transplantation (HR 0.78 per C-allele; 95%-CI 0.67–0.90; P = 0.001). On the other hand, the C-allele of the IL6 SNP (at position-174 in the promoter; rs1800795 G > C) in donor kidneys was associated with an increased risk of rejection for male organ donors (HR per C-allele 1.31; 95%-CI 1.08–1.58; P = 0.0006), but not female organ donors (P = 0.33). In contrast, neither the IL6 nor IL6R SNP in the recipient showed an association with renal transplant rejection. In conclusion, donor IL6 and IL6R genotypes but not recipient genotypes represent an independent prognostic marker for biopsy-proven renal allograft rejection.
A machine learning approach identifies 5-ASA and ulcerative colitis as being linked with higher COVID-19 mortality in patients with IBD
Authors: Roy Satyaki , Sheikh Shehzad Z. , Furey Terrence S. 
Published: August 2021

AbstractInflammatory bowel diseases (IBD), namely Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammation within the gastrointestinal tract. IBD patient conditions and treatments, such as with immunosuppressants, may result in a higher risk of viral and bacterial infection and more severe outcomes of infections. The effect of the clinical and demographic factors on the prognosis of COVID-19 among IBD patients is still a significant area of investigation. The lack of available data on a large set of COVID-19 infected IBD patients has hindered progress. To circumvent this lack of large patient data, we present a random sampling approach to generate clinical COVID-19 outcomes (outpatient management, hospitalized and recovered, and hospitalized and deceased) on 20,000 IBD patients modeled on reported summary statistics obtained from the Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE-IBD), an international database to monitor and report on outcomes of COVID-19 occurring in IBD patients. We apply machine learning approaches to perform a comprehensive analysis of the primary and secondary covariates to predict COVID-19 outcome in IBD patients. Our analysis reveals that age, medication usage and the number of comorbidities are the primary covariates, while IBD severity, smoking history, gender and IBD subtype (CD or UC) are key secondary features. In particular, elderly male patients with ulcerative colitis, several preexisting conditions, and who smoke comprise a highly vulnerable IBD population. Moreover, treatment with 5-ASAs (sulfasalazine/mesalamine) shows a high association with COVID-19/IBD mortality. Supervised machine learning that considers age, number of comorbidities and medication usage can predict COVID-19/IBD outcomes with approximately 70% accuracy. We explore the challenge of drawing demographic inferences from existing COVID-19/IBD data. Overall, there are fewer IBD case reports from US states with poor health ranking hindering these analyses. Generation of patient characteristics based on known summary statistics allows for increased power to detect IBD factors leading to variable COVID-19 outcomes. There is under-reporting of COVID-19 in IBD patients from US states with poor health ranking, underpinning the perils of using the repository to derive demographic information.