bluuebunny/crossref_metadata_2025_split huggingface dataset:
The use of pXRF for light element geochemical analysis: a review of hardware design limitations and an empirical investigation of air, vacuum, helium flush and detector window technologies
Authors: Adams Cameron , Brand Christabel , Dentith Michael , Fiorentini Marco , Caruso Stefano , Mehta Manasvi 
Published: January 2020

Light element data are required for robust and accurate lithogeochemical interpretations and are important components in the study of hydrothermal alteration and mineralization processes. In this contribution we review the latest available portable energy dispersive X-Ray Fluorescence (pXRF) technologies exclusively in the context of light element analysis, with focus on the acquisition of data for Na, Mg, Al and Si. We discuss pXRF hardware design limitations, quantify variables that attenuate X-ray energies through numerical modelling, including common pXRF configurations, and empirically investigate modern pXRF technologies used to mitigate X-ray attenuation and improve light element analysis.
The void between the sample and detector is a key issue regarding the success of pXRF light element analysis. Dry-air (normal conditions), vacuum purge and helium flush systems are evaluated. Modelled data that use a nominal sample-detector void of 10 mm show that using helium in lieu of air improves X-ray transmission effectiveness from ≈2% to ≈99% for Na and ≈10% to ≈100% for Mg. Modelled detector window data show that using a graphene detector window in lieu of a traditional beryllium detector window improves X-ray transmission effectiveness for Na from ≈38% to ≈64% and ≈57% to ≈77% for Mg. Progressive X-ray transmission effectiveness equates to ≈63% Na and ≈76% Mg when using a helium-graphene pXRF configuration v. ≈1% for Na and ≈6% Mg when using a traditional in-air beryllium pXRF arrangement (i.e. without sample or X-ray entrance window media).
Empirically determined improvements of the resolved signal are more modest than those of modelled X-ray transmission effectiveness data. Instrument noise, spectral overlaps and random counting errors are unavoidable and inherent with the limitations of modern detector technologies. However, the employment of helium with graphene detector window technology allows very precise data to be obtained at significantly shorter scan times (i.e. 20 s, instead of the traditional 60–180 s, i.e. 3–9 times faster): a scan time of 20 s can achieve a precision of ≈18% @ ≈0.4% Na and ≈8% @ ≈0.3% Mg for elemental interference-free samples. Precision will improve with increasing analyte concentration.
In Barrett’s epithelial cells, weakly acidic bile salt solutions cause oxidative DNA damage with response and repair mediated by p38
Authors: Huo Xiaofang , Dunbar Kerry B. , Zhang Xi , Zhang Qiuyang , Spechler Stuart Jon , Souza Rhonda F. 
Published: January 2020

The frequency of esophageal adenocarcinoma is rising despite widespread use of proton pump inhibitors (PPIs), which heal reflux esophagitis but do not prevent reflux of weakly acidic gastric juice and bile in Barrett’s esophagus patients. We aimed to determine if weakly acidic (pH 5.5) bile salt medium (WABM) causes DNA damage in Barrett’s cells. Because p53 is inactivated frequently in Barrett’s esophagus and p38 can assume p53 functions, we explored p38’s role in DNA damage response and repair. We exposed Barrett’s cells with or without p53 knockdown to WABM, and evaluated DNA damage, its response and repair, and whether these effects are p38 dependent. We also measured phospho-p38 in biopsies of Barrett’s metaplasia exposed to deoxycholic acid (DCA). WABM caused phospho-H2AX increases that were blocked by a reactive oxygen species (ROS) scavenger. WABM increased phospho-p38 and reduced bromodeoxyuridine incorporation (an index of S phase entry). Repair of WABM-induced DNA damage proceeded through p38-mediated base excision repair (BER) associated with reduction-oxidation factor 1-apurinic/apyrimidinic endonuclease I (Ref-1/APE1). Cells treated with WABM supplemented with ursodeoxycholic acid (UDCA) exhibited enhanced p38-mediated responses to DNA damage. All of these effects were observed in p53-intact and p53-deficient Barrett’s cells. In patients, esophageal DCA perfusion significantly increased phospho-p38 in Barrett’s metaplasia. WABM exposure generates ROS, causing oxidative DNA damage in Barrett’s cells, a mechanism possibly underlying the rising frequency of esophageal adenocarcinoma despite PPI usage. p38 plays a central role in oxidative DNA damage response and Ref-1/APE1-associated BER, suggesting potential chemopreventive roles for agents like UDCA that increase p38 activity in Barrett’s esophagus. NEW & NOTEWORTHY We found that weakly acidic bile salt solutions, with compositions similar to the refluxed gastric juice of gastroesophageal reflux disease patients on proton pump inhibitors, cause oxidative DNA damage in Barrett’s metaplasia that could contribute to the development of esophageal adenocarcinoma. We also have elucidated a critical role for p38 in Barrett’s metaplasia in its response to and repair of oxidative DNA damage, suggesting a potential chemopreventive role for agents like ursodeoxycholic acid that increase p38 activity in Barrett’s esophagus.
Mutational Landscape and Patterns of Clonal Evolution in Relapsed Pediatric Acute Lymphoblastic Leukemia
Authors: Waanders Esmé , Gu Zhaohui , Dobson Stephanie M. , Antić Željko , Crawford Jeremy Chase , Ma Xiaotu , Edmonson Michael N. , Payne-Turner Debbie , van de Vorst Maartje , Jongmans Marjolijn C.J. , McGuire Irina , Zhou Xin , Wang Jian , Shi Lei , Pounds Stanley , Pei Deqing , Cheng Cheng , Song Guangchun , Fan Yiping , Shao Ying , Rusch Michael , McCastlain Kelly , Yu Jiangyan , van Boxtel Ruben , Blokzijl Francis , Iacobucci Ilaria , Roberts Kathryn G. , Wen Ji , Wu Gang , Ma Jing , Easton John , Neale Geoffrey , Olsen Scott R. , Nichols Kim E. , Pui Ching-Hon , Zhang Jinghui , Evans William E. , Relling Mary V. , Yang Jun J. , Thomas Paul G. , Dick John E. , Kuiper Roland P. , Mullighan Charles G. 
Published: January 2020

Abstract

Relapse of acute lymphoblastic leukemia (ALL) remains a leading cause of childhood cancer-related death. Prior studies have shown clonal mutations at relapse often arise from relapse-fated subclones that exist at diagnosis. However, the genomic landscape, evolutionary trajectories, and mutational mechanisms driving relapse are incompletely understood. In an analysis of 92 cases of relapsed childhood ALL incorporating multimodal DNA and RNA sequencing, deep digital mutational tracking, and xenografting to formally define clonal structure, we identified 50 significant targets of mutation with distinct patterns of mutational acquisition or enrichment. CREBBP, NOTCH1, and RAS signaling mutations arose from diagnosis subclones, whereas variants in NCOR2, USH2A, and NT5C2 were exclusively observed at relapse. Evolutionary modeling and xenografting demonstrated that relapse-fated clones were minor (50%), major (27%), or multiclonal (18%) at diagnosis. Putative second leukemias, including those with lineage shift, were shown to most commonly represent relapse from an ancestral clone rather than a truly independent second primary leukemia. A subset of leukemias prone to repeated relapse exhibited hypermutation driven by at least three distinct mutational processes, resulting in heightened neoepitope burden and potential vulnerability to immunotherapy. Finally, relapse-driving sequence mutations were detected prior to relapse using droplet digital PCR at levels comparable with orthogonal approaches to monitor levels of measurable residual disease. These results provide a genomic framework to anticipate and circumvent relapse by earlier detection and targeting of relapse-fated clones.

Significance:
This study defines the landscape of mutations that preexist and arise after commencement of ALL therapy and shows that relapse may be propagated from ancestral, major, or minor clones at initial diagnosis. A subset of cases exhibits hypermutation that results in expression of neoepitopes that may be substrates for immunotherapeutic intervention.
See related video: https://vimeo.com/442838617
See related commentary by Ogawa, p. 21.
See related article by S. Dobson et al .
This article is highlighted in the In This Issue feature, p. 5
The Tumor Suppressor BAP1 Regulates the Hippo Pathway in Pancreatic Ductal Adenocarcinoma
Authors: Lee Ho-June , Pham Trang , Chang Matthew T. , Barnes Dwight , Cai Allen G. , Noubade Rajkumar , Totpal Klara , Chen Xu , Tran Christopher , Hagenbeek Thijs , Wu Xiumin , Eastham-Anderson Jeff , Tao Janet , Lee Wyne , Bastian Boris C. , Carbone Michele , Webster Joshua D. , Dey Anwesha 
Published: January 2020

Abstract

The deubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with a high risk for mesothelioma and melanocytic tumors. Here, we show that pancreatic intraepithelial neoplasia driven by oncogenic mutant KrasG12D progressed to pancreatic adenocarcinoma in the absence of BAP1. The Hippo pathway was deregulated in BAP1-deficient pancreatic tumors, with the tumor suppressor LATS exhibiting enhanced ubiquitin-dependent proteasomal degradation. Therefore, BAP1 may limit tumor progression by stabilizing LATS and thereby promoting activity of the Hippo tumor suppressor pathway.

Significance:
BAP1 is mutated in a broad spectrum of tumors. Pancreatic Bap1 deficiency causes acinar atrophy but combines with oncogenic Ras to produce pancreatic tumors. BAP1-deficient tumors exhibit deregulation of the Hippo pathway.
See related commentary by Brekken, p. 1624
Biomarkers of Exposure among Adult Smokeless Tobacco Users in the Population Assessment of Tobacco and Health Study (Wave 1, 2013–2014)
Authors: Cheng Yu-Ching , Reyes-Guzman Carolyn M. , Christensen Carol H. , Rostron Brian L. , Edwards Kathryn C. , Wang Lanqing , Feng Jun , Jarrett Jeffery M. , Ward Cynthia D. , Xia Baoyun , Kimmel Heather L. , Conway Kevin , Leggett Carmine , Taylor Kristie , Lawrence Charlie , Niaura Ray , Travers Mark J. , Hyland Andrew , Hecht Stephen S. , Hatsukami Dorothy K. , Goniewicz Maciej L. , Borek Nicolette , Blount Benjamin C. , van Bemmel Dana M. 
Published: January 2020

Abstract

Background:
Monitoring population-level toxicant exposures from smokeless tobacco (SLT) use is important for assessing population health risks due to product use. In this study, we assessed tobacco biomarkers of exposure (BOE) among SLT users from the Wave 1 (2013–2014) of the Population Assessment of Tobacco and Health (PATH) Study.

Methods:
Urinary biospecimens were collected from adults ages 18 and older. Biomarkers of nicotine, tobacco-specific nitrosamines (TSNA), polycyclic aromatic hydrocarbons (PAH), volatile organic compounds (VOC), metals, and inorganic arsenic were analyzed and reported among exclusive current established SLT users in comparison with exclusive current established cigarette smokers, dual SLT and cigarette users, and never tobacco users.

Results:
In general, SLT users (n = 448) have significantly higher concentrations of BOE to nicotine, TSNAs, and PAHs compared with never tobacco users; significant dose–response relationships between frequency of SLT use and biomarker concentrations were also reported among exclusive SLT daily users. Exclusive SLT daily users have higher geometric mean concentrations of total nicotine equivalent-2 (TNE2) and TSNAs than exclusive cigarette daily smokers. In contrast, geometric mean concentrations of PAHs and VOCs were substantially lower among exclusive SLT daily users than exclusive cigarette daily smokers.

Conclusions:
Our study produced a comprehensive assessment of SLT product use and 52 biomarkers of tobacco exposure. Compared with cigarette smokers, SLT users experience greater concentrations of some tobacco toxicants, including nicotine and TSNAs.

Impact:
Our data add information on the risk assessment of exposure to SLT-related toxicants. High levels of harmful constituents in SLT remain a health concern.
Genetic Predisposition to Colon and Rectal Adenocarcinoma Is Mediated by a Super-enhancer Polymorphism CoactivatingCD9andPLEKHG6
Authors: Ke Juntao , Tian Jianbo , Mei Shufang , Ying Pingting , Yang Nan , Wang Xiaoyang , Zou Danyi , Peng Xiating , Yang Yang , Zhu Ying , Gong Yajie , Wang Zhihua , Gong Jing , Zhong Rong , Chang Jiang , Miao Xiaoping 
Published: January 2020

AbstractBackground:Genome-wide association studies (GWAS) have identified dozens of loci associated with colon and rectal adenocarcinoma risk. As tissue-specific super-enhancers (SE) play important roles in tumorigenesis, we systematically investigate SEs and inner variants in established GWAS loci to decipher the underlying biological mechanisms.Methods:Through a comprehensive bioinformatics analysis on multi-omics data, we screen potential single-nucleotide polymorphisms (SNP) in cancer-specific SEs, and then subject them to a two-stage case–control study containing 4,929 cases and 7,083 controls from the Chinese population. A series of functional assays, including reporter gene assays, electrophoretic mobility shift assays (EMSA), CRISPR–Cas9 genome editing, chromosome conformation capture (3C) assays, and cell proliferation experiments, are performed to characterize the variant's molecular consequence and target genes.Results:The SNP rs11064124 in 12p13.31 is found significantly associated with the risk of colon and rectal adenocarcinoma with an odds ratio (OR) of 0.87 [95% confidence interval (CI), 0.82–0.92, P = 8.67E-06]. The protective rs11064124-G weakens the binding affinity with vitamin D receptor (VDR) and increases the enhancer's activity and interactions with two target genes' promoters, thus coactivating the transcription of CD9 and PLEKHG6, which are both putative tumor suppressor genes for colon and rectal adenocarcinoma.Conclusions:Our integrative study highlights an SE polymorphism rs11064124 and two susceptibility genes CD9 and PLEKHG6 in 12p13.31 for colon and rectal adenocarcinoma.Impact:These findings suggest a novel insight for genetic pathogenesis of colon and rectal adenocarcinoma, involving transcriptional coactivation of diverse susceptibility genes via the SE element as a gene regulation hub.
Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy
Authors: Mazzarotto Francesco , Tayal Upasana , Buchan Rachel J. , Midwinter William , Wilk Alicja , Whiffin Nicola , Govind Risha , Mazaika Erica , de Marvao Antonio , Dawes Timothy J.W. , Felkin Leanne E. , Ahmad Mian , Theotokis Pantazis I. , Edwards Elizabeth , Ing Alexander Y. , Thomson Kate L. , Chan Laura L.H. , Sim David , Baksi A. John , Pantazis Antonis , Roberts Angharad M. , Watkins Hugh , Funke Birgit , O’Regan Declan P. , Olivotto Iacopo , Barton Paul J.R. , Prasad Sanjay K. , Cook Stuart A. , Ware James S. , Walsh Roddy 
Published: January 2020

Background:
Dilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories. However, many genes were originally identified based on candidate-gene studies that did not adequately account for background population variation. Here we define the frequency of rare variation in 2538 patients with DCM across protein-coding regions of 56 commonly tested genes and compare this to both 912 confirmed healthy controls and a reference population of 60 706 individuals to identify clinically interpretable genes robustly associated with dominant monogenic DCM.

Methods:
We used the TruSight Cardio sequencing panel to evaluate the burden of rare variants in 56 putative DCM genes in 1040 patients with DCM and 912 healthy volunteers processed with identical sequencing and bioinformatics pipelines. We further aggregated data from 1498 patients with DCM sequenced in diagnostic laboratories and the Exome Aggregation Consortium database for replication and meta-analysis.

Results:

Truncating variants in
TTN
and
DSP
were associated with DCM in all comparisons. Variants in
MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1
, and
VCL
were significantly enriched in specific patient subsets, with the last 2 genes potentially contributing primarily to early-onset forms of DCM. Overall, rare variants in these 12 genes potentially explained 17% of cases in the outpatient clinic cohort representing a broad range of adult patients with DCM and 26% of cases in the diagnostic referral cohort enriched in familial and early-onset DCM. Although the absence of a significant excess in other genes cannot preclude a limited role in disease, such genes have limited diagnostic value because novel variants will be uninterpretable and their diagnostic yield is minimal.

Conclusions:
In the largest sequenced DCM cohort yet described, we observe robust disease association with 12 genes, highlighting their importance in DCM and translating into high interpretability in diagnostic testing. The other genes analyzed here will need to be rigorously evaluated in ongoing curation efforts to determine their validity as Mendelian DCM genes but have limited value in diagnostic testing in DCM at present. This data will contribute to community gene curation efforts and will reduce erroneous and inconclusive findings in diagnostic testing.
An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome
Authors: Adler Arnon , Novelli Valeria , Amin Ahmad S. , Abiusi Emanuela , Care Melanie , Nannenberg Eline A. , Feilotter Harriet , Amenta Simona , Mazza Daniela , Bikker Hennie , Sturm Amy C. , Garcia John , Ackerman Michael J. , Hershberger Raymond E. , Perez Marco V. , Zareba Wojciech , Ware James S. , Wilde Arthur A.M. , Gollob Michael H. 
Published: January 2020

Background:
Long QT syndrome (LQTS) is the first described and most common inherited arrhythmia. Over the last 25 years, multiple genes have been reported to cause this condition and are routinely tested in patients. Because of dramatic changes in our understanding of human genetic variation, reappraisal of reported genetic causes for LQTS is required.

Methods:
Utilizing an evidence-based framework, 3 gene curation teams blinded to each other’s work scored the level of evidence for 17 genes reported to cause LQTS. A Clinical Domain Channelopathy Working Group provided a final classification of these genes for causation of LQTS after assessment of the evidence scored by the independent curation teams.

Results:

Of 17 genes reported as being causative for LQTS, 9 (
AKAP9, ANK2, CAV3, KCNE1, KCNE2, KCNJ2, KCNJ5, SCN4B, SNTA1
) were classified as having limited or disputed evidence as LQTS-causative genes. Only 3 genes (
KCNQ1, KCNH2, SCN5A
) were curated as definitive genes for typical LQTS. Another 4 genes (
CALM1, CALM2, CALM3, TRDN
) were found to have strong or definitive evidence for causality in LQTS with atypical features, including neonatal atrioventricular block. The remaining gene (
CACNA1C
) had moderate level evidence for causing LQTS.

Conclusions:
More than half of the genes reported as causing LQTS have limited or disputed evidence to support their disease causation. Genetic variants in these genes should not be used for clinical decision-making, unless accompanied by new and sufficient genetic evidence. The findings of insufficient evidence to support gene-disease associations may extend to other disciplines of medicine and warrants a contemporary evidence-based evaluation for previously reported disease-causing genes to ensure their appropriate use in precision medicine.
The Building Blocks of Northern Hemisphere Wintertime Stationary Waves
Authors: Garfinkel Chaim I. , White Ian , Gerber Edwin P. , Jucker Martin , Erez Moran 
Published: January 2020

AbstractAn intermediate-complexity moist general circulation model is used to investigate the forcing of stationary waves in the Northern Hemisphere boreal winter by land–sea contrast, horizontal heat fluxes in the ocean, and topography. The additivity of the response to these building blocks is investigated. In the Pacific sector, the stationary wave pattern is not simply the linear additive sum of the response to each forcing. In fact, over the northeast Pacific and western North America, the sum of the responses to each forcing is actually opposite to that when all three are imposed simultaneously due to nonlinear interactions among the forcings. The source of the nonlinearity is diagnosed using the zonally anomalous steady-state thermodynamic balance, and it is shown that the background-state temperature field set up by each forcing dictates the stationary wave response to the other forcings. As all three forcings considered here strongly impact the temperature field and its zonal gradients, the nonlinearity and nonadditivity in our experiments can be explained, but only in a diagnostic sense. This nonadditivity extends up to the stratosphere, and also to surface temperature, where the sum of the responses to each forcing differs from the response if all forcings are included simultaneously. Only over western Eurasia is additivity a reasonable (though not perfect) assumption; in this sector land–sea contrast is most important over Europe, while topography is most important over western Asia. In other regions, where nonadditivity is pronounced, the question of which forcing is most important is ill-posed.
Dissipation of Turbulent Kinetic Energy in the Oscillating Bottom Boundary Layer of a Large Shallow Lake
Authors: Jabbari Aidin , Boegman Leon , Valipour Reza , Wain Danielle , Bouffard Damien 
Published: January 2020

AbstractMixing rates and biogeochemical fluxes are commonly estimated from the rate of dissipation of turbulent kinetic energy ε as measured with a single instrument and processing method. However, differences in measurements of ε between instruments/methods often vary by one order of magnitude. In an effort to identify error in computing ε, we have applied four common methods to data from the bottom boundary layer of Lake Erie. We applied the second-order structure function method (SFM) to velocity measurements from an acoustic Doppler current profiler, using both canonical and anisotropy-adjusted Kolmogorov constants, and compared the results with those computed from the law of the wall, Batchelor fitting to temperature gradient microstructure, and inertial subrange fitting to acoustic Doppler velocimeter data. The ε from anisotropy-adjusted constants in SFM increased by a factor of 6 or more at 0.2 m above the bed and showed a better agreement with microstructure and inertial method estimations. The maximum difference between SFM ε, computed using adjusted and canonical constants, and microstructure values was 25% and 50%, respectively. This difference was 30% and 55%, respectively, for those from inertial subrange fitting at times of high-intensity turbulence (Reynolds number at 1 m above the bed of more than 2 × 104). Comparison of the SFM ε to those from law of the wall was often poor, with errors as large as one order of magnitude. From the considerable improvement in ε estimates near the bed, anisotropy-adjusted Kolmogorov constants should be applied to compute dissipation in geophysical boundary layers.