bluuebunny/crossref_metadata_2025_split huggingface dataset:
Constraints on Early Paleozoic Deep‐Ocean Oxygen Concentrations From the Iron Geochemistry of the Bay of Islands Ophiolite
Authors: Stolper Daniel A. , Pu Xiaofei , Lloyd Max K. , Christensen Nikolas I. , Bucholz Claire E. , Lange Rebecca A. 
Published: June 2022

AbstractThe deep ocean is generally considered to have changed from anoxic in the Precambrian to oxygenated by the Late Paleozoic (∼420–400 Ma) due to changes in atmospheric oxygen concentrations. When the transition occurred, that is, in the Early Paleozoic or not until the Late Paleozoic, is less well constrained. To address this, we measured Fe3+/ΣFe of volcanic rocks, sheeted dykes, gabbros, and ultramafic rocks from the Early Paleozoic (∼485 Ma) Bay of Islands (BOI) ophiolite as a proxy for hydrothermal alteration in the presence or absence of O2derived from deep marine fluids. Combining this data with previously published data from the BOI indicates that volcanic rocks are oxidized relative to intrusive crustal rocks (0.35 ± 0.02 vs. 0.19 ± 0.01, 1 standard error), which we interpret to indicate that the volcanic section was altered by marine‐derived fluids that contained some dissolved O2. We compare our results directly to the Macquarie Island and Troodos ophiolites, drilled oceanic crust, previously compiled data for ophiolitic volcanic rocks, and newly compiled data for ophiolitic intrusive rocks. These comparisons show that the BOI volcanic (but not intrusive) rocks are oxidized relative to Precambrian equivalents, but are less oxidized relative to Late Paleozoic to modern equivalents. We interpret these results to indicate that the Early Paleozoic ocean contained dissolved O2, but at concentrations ∼2.4× lower than for the Late Paleozoic to today.
Seismic Imaging of Crust Beneath the Western Tibet‐Pamir and Western Himalaya Using Ambient Noise and Earthquake Data
Authors: Kumar Vivek , Rai Shyam S. , Hawkins Rhys , Bodin Thomas 
Published: June 2022

AbstractWe present a new high‐resolution image of the crust beneath the western Himalaya‐Asia convergence zone encompassing the geographical domain of western Himalaya‐western Tibet‐Ladakh‐Karakoram‐Pamir‐Hindu Kush, using ambient noise cross‐correlations from 530 seismological stations along with surface wave observations from 1,261 earthquakes recorded over the network. The 3‐D shear wave velocity image is created using 22,726 inter‐station Rayleigh wave dispersion measurements from 5 to 60 s period at a horizontal resolution of less than 0.5° × 0.5° following the Bayesian Trans‐dimensional Tree tomography approach. The Moho beneath the Himalayas and south Tibet correlates with a velocity transition of 4.4–4.6 km/s and a reduced velocity transition of 4.0–4.2 km/s in northern Tibet and the Pamir. We used the Moho depth and the nature of high‐velocity lower crust (Vs > 4.0 km/s) to map the northern limit of the Indian crust that extends beyond the Qiangtang block in western Tibet (77–82°E) from its previously assumed boundary in the Lhasa block and till the central Pamir farther west. The velocity image reveals discontinuous low‐velocity zones (LVZs; Vs < 3.4 km/s) in the mid‐crust of western Tibet and the Pamir that do not support the existence of the channel flow model. The LVZs in the Pamir correlate with the surface distribution of gneiss domes. The lowest velocities (Vs < 3.2 km/s) are observed over the Ladakh‐Karakoram batholith and the Nanga Parbat region. The study suggests a continuation of LVZs across the Karakoram Fault at a depth below 20 km, indicating the fault's upper crustal depth extent.
Subpolar Southern Ocean Seasonal Variability of the Geostrophic Circulation From Multi‐Mission Satellite Altimetry
Authors: Auger Matthis , Sallée Jean‐Baptiste , Prandi Pierre , Naveira Garabato Alberto C. 
Published: June 2022

AbstractA novel multi‐satellite product is used to shed light on the sea surface height seasonal cycle and associated geostrophic circulation in the subpolar Southern Ocean. We find three main modes of variability governing the Sea Level Anomaly seasonal cycle, all of them primarily governed by wind forcing. The main mode of seasonal variability is associated with the seasonality of the main subpolar gyres governed by large‐scale wind stress curl, qualitatively consistent with Sverdrup dynamics. The second seasonal mode is related to the Antarctic Slope Current (ASC), governed by the coastal easterlies, with a rapid circumpolar propagation of anomalous sea‐level along the continental slope that is dynamically consistent with the so‐called Southern Mode. The first two modes induce an acceleration of the gyres and the ASC in winter. The third seasonal mode appears to be driven by sea ice‐modulated surface stress and induces an offshore extension of the ASC from autumn to winter.
Maintenance therapy for acute lymphoblastic leukemia: basic science and clinical translations
Authors: Toksvang Linea N. , Lee Shawn H. R. , Yang Jun J. , Schmiegelow Kjeld 
Published: June 2022

AbstractMaintenance therapy (MT) with oral methotrexate (MTX) and 6-mercaptopurine (6-MP) is essential for the cure of acute lymphoblastic leukemia (ALL). MTX and 6-MP interfere with nucleotide synthesis and salvage pathways. The primary cytotoxic mechanism involves the incorporation of thioguanine nucleotides (TGNs) into DNA (as DNA-TG), which may be enhanced by the inhibition of de novo purine synthesis by other MTX/6-MP metabolites. Co-medication during MT is common. Although Pneumocystis jirovecii prophylaxis appears safe, the benefit of glucocorticosteroid/vincristine pulses in improving survival and of allopurinol to moderate 6-MP pharmacokinetics remains uncertain. Numerous genetic polymorphisms influence the pharmacology, efficacy, and toxicity (mainly myelosuppression and hepatotoxicity) of MTX and thiopurines. Thiopurine S-methyltransferase (encoded by TPMT) decreases TGNs but increases methylated 6-MP metabolites (MeMPs); similarly, nudix hydrolase 15 (encoded by NUDT15) also decreases TGNs available for DNA incorporation. Loss-of-function variants in both genes are currently used to guide MT, but do not fully explain the inter-patient variability in thiopurine toxicity. Because of the large inter-individual variations in MTX/6-MP bioavailability and metabolism, dose adjustments are traditionally guided by the degree of myelosuppression, but this does not accurately reflect treatment intensity. DNA-TG is a common downstream metabolite of MTX/6-MP combination chemotherapy, and a higher level of DNA-TG has been associated with a lower relapse hazard, leading to the development of the Thiopurine Enhanced ALL Maintenance (TEAM) strategy—the addition of low-dose (2.5–12.5 mg/m2/day) 6-thioguanine to the 6-MP/MTX backbone—that is currently being tested in a randomized ALLTogether1 trial (EudraCT: 2018-001795-38). Mutations in the thiopurine and MTX metabolism pathways, and in the mismatch repair genes have been identified in early ALL relapses, providing valuable insights to assist the development of strategies to detect imminent relapse, to facilitate relapse salvage therapy, and even to bring about changes in frontline ALL therapy to mitigate this relapse risk.
Accelerated epigenetic aging in suicide attempters uninfluenced by high intent-to-die and choice of lethal methods
Authors: Jokinen Jussi , Andersson Peter , Chatzittofis Andreas , Savard Josephine , Rask-Andersen Mathias , Åsberg Marie , Boström Adrian Desai E. 
Published: June 2022

AbstractSuicide attempts (SA) are associated with excess non-suicidal mortality, putatively mediated in part by premature cellular senescence. Epigenetic age (EA) estimators of biological age have been previously demonstrated to strongly predict physiological dysregulation and mortality risk. Herein, we investigate if violent SA with high intent-to-die is predictive of epigenetics-derived estimates of biological aging. The genome-wide methylation pattern was measured using the Illumina Infinium Methylation EPIC BeadChip in whole blood of 88 suicide attempters. Subjects were stratified into two groups based on the putative risk of later committed suicide (low- [n = 58] and high-risk [n = 30]) in dependency of SA method (violent or non-violent) and/or intent-to-die (high/low). Estimators of intrinsic and extrinsic EA acceleration, one marker optimized to predict physiological dysregulation (DNAmPhenoAge/AgeAccelPheno) and one optimized to predict lifespan (DNAmGrimAge/AgeAccelGrim) were investigated for associations to severity of SA, by univariate and multivariate analyses. The study was adequately powered to detect differences of 2.2 years in AgeAccelGrim in relation to SA severity. Baseline DNAmGrimAge exceeded chronological age by 7.3 years on average across all samples, conferring a mean 24.6% increase in relation to actual age. No individual EA acceleration marker was differentiated by suicidal risk group (p > 0.1). Thus, SA per se but not severity of SA is related to EA, implicating that excess non-suicidal mortality in SA is unrelated to risk of committed suicide. Preventative healthcare efforts aimed at curtailing excess mortality after SA may benefit from acting equally powerful to recognize somatic comorbidities irrespective of the severity inherent in the act itself.
Transcription factor SNAI2 exerts pro-tumorigenic effects on glioma stem cells via PHLPP2-mediated Akt pathway
Authors: Peng Lilei , Fu Jie , Chen Yitian , Ming Yang , He Haiping , Zeng Shan , Zhong Chuanhong , Chen Ligang 
Published: June 2022

AbstractThe current study aimed to investigate the effects associated with SNAI2 on the proliferation of glioma stem cells (GSCs) to elucidate its underlying molecular mechanism in the development of glioma. The expression of Snail family transcriptional repressor 2 (SNAI2) in glioma tissues was initially predicted via bioinformatics analysis and subsequently confirmed by reverse transcription quantitative polymerase chain reaction (RT-qPCR), which revealed that SNAI2 was highly expressed in glioma tissues as well as GSCs, with an inverse correlation with overall glioma patient survival detected. Loss- and gain- of-function assays were performed to determine the roles of SNAI2 and pleckstrin homology domain and leucine rich repeat protein phosphatase 2 (PHLPP2) on GSC viability, proliferation and apoptosis. Data were obtained indicating that SNAI2 promoted the proliferation of GSCs, while overexpressed PHLPP2 brought about a contrasting trend. As detected by chromatin immunoprecipitation, RT-qPCR and agarose gel electrophoresis, SNAI2 bound to the promoter region of PHLPP2 and repressed the transcription of PHLPP2 while SNAI2 was found to inhibit PHLPP2 resulting in activation of the Akt pathway. Finally, the roles of SNAI2 and PHLPP2 were verified in glioma growth in nude mice xenografted with tumor. Taken together, the key findings of the present study suggest that SNAI2 may promote the proliferation of GSCs through activation of the Akt pathway by downregulating PHLPP2.
Essential role of Rnd1 in innate immunity during viral and bacterial infections
Authors: Kumar Akhilesh , Mishra Shalabh , Kumar Ashish , Raut Ashwin Ashok , Sato Seiichi , Takaoka Akinori , Kumar Himanshu 
Published: June 2022

AbstractIntracellular and cell surface pattern-recognition receptors (PRRs) are an essential part of innate immune recognition and host defense. Here, we have compared the innate immune responses between humans and bats to identify a novel membrane-associated protein, Rnd1, which defends against viral and bacterial infection in an interferon-independent manner. Rnd1 belongs to the Rho GTPase family, but unlike other small GTPase members, it is constitutively active. We show that Rnd1 is induced by pro-inflammatory cytokines during viral and bacterial infections and provides protection against these pathogens through two distinct mechanisms. Rnd1 counteracts intracellular calcium fluctuations by inhibiting RhoA activation, thereby inhibiting virus internalisation. On the other hand, Rnd1 also facilitates pro-inflammatory cytokines IL-6 and TNF-α through Plxnb1, which are highly effective against intracellular bacterial infections. These data provide a novel Rnd1-mediated innate defense against viral and bacterial infections.
Induction of autophagy-dependent ferroptosis to eliminate drug-tolerant human retinoblastoma cells
Authors: Liu Ke , Huang Jun , Liu Jiao , Klionsky Daniel J. , Kang Rui , Tang Daolin 
Published: June 2022

AbstractCarboplatin is the most used first-line drug for the treatment of human retinoblastoma (RB), a rare form of cancer in infancy and childhood. However, the clinical application of carboplatin is restricted due to the emergence of acquired multi-drug resistance (MDR) after long-term treatment. Here, we report a new strategy to eliminate MDR RB cells by inducing autophagy-dependent ferroptosis. Compared with parent cells, carboplatin-resistant human RB cells have higher autophagy activity, which drives the formation of MDR to other chemotherapeutic drugs (e.g., etoposide and vincristine). In addition to confirming the traditional strategy of inhibiting autophagy to overcome MDR, we also establish an approach of inducing selective ferritinophagy to eliminate drug-resistant cells. We evaluate the effectiveness and safety of 4-octyl itaconate, a cell-permeable derivative of the metabolite itaconate, in inducing ferritinophagy-dependent ferroptosis in the treatment of MDR RB cells in vitro and in xenograft mouse models. These findings may provide essential clues for initiating clinical trials that target autophagy-dependent ferroptosis to kill drug-tolerant persistent cells during RB therapy.
A role for microfluidic systems in precision medicine
Authors: Ayuso Jose M. , Virumbrales-Muñoz María , Lang Joshua M. , Beebe David J. 
Published: June 2022

AbstractPrecision oncology continues to challenge the “one-size-fits-all” dogma. Under the precision oncology banner, cancer patients are screened for molecular tumor alterations that predict treatment response, ideally leading to optimal treatments. Functional assays that directly evaluate treatment efficacy on the patient’s cells offer an alternative and complementary tool to improve the accuracy of precision oncology. Unfortunately, traditional Petri dish-based assays overlook much tumor complexity, limiting their potential as predictive functional biomarkers. Here, we review past applications of microfluidic systems for precision medicine and discuss the present and potential future role of functional microfluidic assays as treatment predictors.
Mistargeting of aggregation prone mitochondrial proteins activates a nucleus-mediated posttranscriptional quality control pathway in trypanosomes
Authors: Dewar Caroline E. , Oeljeklaus Silke , Mani Jan , Mühlhäuser Wignand W. D. , von Känel Corinne , Zimmermann Johannes , Ochsenreiter Torsten , Warscheid Bettina , Schneider André 
Published: June 2022

AbstractMitochondrial protein import in the parasitic protozoanTrypanosoma bruceiis mediated by the atypical outer membrane translocase, ATOM. It consists of seven subunits including ATOM69, the import receptor for hydrophobic proteins. Ablation of ATOM69, but not of any other subunit, triggers a unique quality control pathway resulting in the proteasomal degradation of non-imported mitochondrial proteins. The process requires a protein of unknown function, an E3 ubiquitin ligase and the ubiquitin-like protein (TbUbL1), which all are recruited to the mitochondrion upon ATOM69 depletion. TbUbL1 is a nuclear protein, a fraction of which is released to the cytosol upon triggering of the pathway. Nuclear release is essential as cytosolic TbUbL1 can bind mislocalised mitochondrial proteins and likely transfers them to the proteasome. Mitochondrial quality control has previously been studied in yeast and metazoans. Finding such a pathway in the highly diverged trypanosomes suggests such pathways are an obligate feature of all eukaryotes.
Stress routes clients to the proteasome via a BAG2 ubiquitin-independent degradation condensate
Authors: Carrettiero Daniel C. , Almeida Maria C. , Longhini Andrew P. , Rauch Jennifer N. , Han Dasol , Zhang Xuemei , Najafi Saeed , Gestwicki Jason E. , Kosik Kenneth S. 
Published: June 2022

AbstractThe formation of membraneless organelles can be a proteotoxic stress control mechanism that locally condenses a set of components capable of mediating protein degradation decisions. The breadth of mechanisms by which cells respond to stressors and form specific functional types of membraneless organelles, is incompletely understood. We found that Bcl2-associated athanogene 2 (BAG2) marks a distinct phase-separated membraneless organelle, triggered by several forms of stress, particularly hyper-osmotic stress. Distinct from well-known condensates such as stress granules and processing bodies, BAG2-containing granules lack RNA, lack ubiquitin and promote client degradation in a ubiquitin-independent manner via the 20S proteasome. These organelles protect the viability of cells from stress and can traffic to the client protein, in the case of Tau protein, on the microtubule. Components of these ubiquitin-independent degradation organelles include the chaperone HSP-70 and the 20S proteasome activated by members of the PA28 (PMSE) family. BAG2 condensates did not co-localize with LAMP-1 or p62/SQSTM1. When the proteasome is inhibited, BAG2 condensates and the autophagy markers traffic to an aggresome-like structure.
Estimating tumor mutational burden from RNA-sequencing without a matched-normal sample
Authors: Katzir Rotem , Rudberg Noam , Yizhak Keren 
Published: June 2022

AbstractDetection of somatic mutations using patients sequencing data has many clinical applications, including the identification of cancer driver genes, detection of mutational signatures, and estimation of tumor mutational burden (TMB). We have previously developed a tool for detection of somatic mutations using tumor RNA and a matched-normal DNA. Here, we further extend it to detect somatic mutations from RNA sequencing data without a matched-normal sample. This is accomplished via a machine-learning approach that classifies mutations as either somatic or germline based on various features. When applied to RNA-sequencing of >450 melanoma samples high precision and recall are achieved, and both mutational signatures and driver genes are correctly identified. Finally, we show that RNA-based TMB is significantly associated with patient survival, showing similar or higher significance level as compared to DNA-based TMB. Our pipeline can be utilized in many future applications, analyzing novel and existing datasets where only RNA is available.
Evidence for pressure induced unconventional quantum criticality in the coupled spin ladder antiferromagnet C9H18N2CuBr4
Authors: Hong Tao , Ying Tao , Huang Qing , Dissanayake Sachith E. , Qiu Yiming , Turnbull Mark M. , Podlesnyak Andrey A. , Wu Yan , Cao Huibo , Liu Yaohua , Umehara Izuru , Gouchi Jun , Uwatoko Yoshiya , Matsuda Masaaki , Tennant David A. , Chern Gia-Wei , Schmidt Kai P. , Wessel Stefan 
Published: June 2022

AbstractQuantum phase transitions in quantum matter occur at zero temperature between distinct ground states by tuning a nonthermal control parameter. Often, they can be accurately described within the Landau theory of phase transitions, similarly to conventional thermal phase transitions. However, this picture can break down under certain circumstances. Here, we present a comprehensive study of the effect of hydrostatic pressure on the magnetic structure and spin dynamics of the spin-1/2 ladder compound C9H18N2CuBr4. Single-crystal heat capacity and neutron diffraction measurements reveal that the Néel-ordered phase breaks down beyond a critical pressure of Pc ∼ 1.0 GPa through a continuous quantum phase transition. Estimates of the critical exponents suggest that this transition may fall outside the traditional Landau paradigm. The inelastic neutron scattering spectra at 1.3 GPa are characterized by two well-separated gapped modes, including one continuum-like and another resolution-limited excitation in distinct scattering channels, which further indicates an exotic quantum-disordered phase above Pc.
The microbiome of cryospheric ecosystems
Authors: Bourquin Massimo , Busi Susheel Bhanu , Fodelianakis Stilianos , Peter Hannes , Washburne Alex , Kohler Tyler J. , Ezzat Leïla , Michoud Grégoire , Wilmes Paul , Battin Tom J. 
Published: June 2022

AbstractThe melting of the cryosphere is among the most conspicuous consequences of climate change, with impacts on microbial life and related biogeochemistry. However, we are missing a systematic understanding of microbiome structure and function across cryospheric ecosystems. Here, we present a global inventory of the microbiome from snow, ice, permafrost soils, and both coastal and freshwater ecosystems under glacier influence. Combining phylogenetic and taxonomic approaches, we find that these cryospheric ecosystems, despite their particularities, share a microbiome with representatives across the bacterial tree of life and apparent signatures of early and constrained radiation. In addition, we use metagenomic analyses to define the genetic repertoire of cryospheric bacteria. Our work provides a reference resource for future studies on climate change microbiology.
Parental inflammatory bowel disease and autism in children
Authors: Sadik Aws , Dardani Christina , Pagoni Panagiota , Havdahl Alexandra , Stergiakouli Evie ,   The iPSYCH Autism Spectrum Disorder Working Group, Grove Jakob , Khandaker Golam M. , Sullivan Sarah A. , Zammit Stan , Jones Hannah J. , Davey Smith George , Dalman Christina , Karlsson Håkan , Gardner Renee M. , Rai Dheeraj 
Published: June 2022

AbstractEvidence linking parental inflammatory bowel disease (IBD) with autism in children is inconclusive. We conducted four complementary studies to investigate associations between parental IBD and autism in children, and elucidated their underlying etiology. Conducting a nationwide population-based cohort study using Swedish registers, we found evidence of associations between parental diagnoses of IBD and autism in children. Polygenic risk score analyses of the Avon Longitudinal Study of Parents and Children suggested associations between maternal genetic liability to IBD and autistic traits in children. Two-sample Mendelian randomization analyses provided evidence of a potential causal effect of genetic liability to IBD, especially ulcerative colitis, on autism. Linkage disequilibrium score regression did not indicate a genetic correlation between IBD and autism. Triangulating evidence from these four complementary approaches, we found evidence of a potential causal link between parental, particularly maternal, IBD and autism in children. Perinatal immune dysregulation, micronutrient malabsorption and anemia may be implicated.