bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation-induced cytidine deaminase localizes to G-quadruplex motifs at mutation hotspots in lymphoma
Authors: Xu Ying-Zhi , Jenjaroenpun Piroon , Wongsurawat Thidathip , Byrum Stephanie D , Shponka Volodymyr , Tannahill David , Chavez Elizabeth A , Hung Stacy S , Steidl Christian , Balasubramanian Shankar , Rimsza Lisa M , Kendrick Samantha 
Published: October 2020

Abstract
Diffuse large B-cell lymphoma (DLBCL) is a molecularly heterogeneous group of malignancies with frequent genetic abnormalities. G-quadruplex (G4) DNA structures may facilitate this genomic instability through association with activation-induced cytidine deaminase (AID), an antibody diversification enzyme implicated in mutation of oncogenes in B-cell lymphomas. Chromatin immunoprecipitation sequencing analyses in this study revealed that AID hotspots in both activated B cells and lymphoma cells in vitro were highly enriched for G4 elements. A representative set of these targeted sequences was validated for characteristic, stable G4 structure formation including previously unknown G4s in lymphoma-associated genes, CBFA2T3, SPIB, BCL6, HLA-DRB5 and MEF2C, along with the established BCL2 and MYC structures. Frequent genome-wide G4 formation was also detected for the first time in DLBCL patient-derived tissues using BG4, a structure-specific G4 antibody. Tumors with greater staining were more likely to have concurrent BCL2 and MYC oncogene amplification and BCL2 mutations. Ninety-seven percent of the BCL2 mutations occurred within G4 sites that overlapped with AID binding. G4 localization at sites of mutation, and within aggressive DLBCL tumors harboring amplified BCL2 and MYC, supports a role for G4 structures in events that lead to a loss of genomic integrity, a critical step in B-cell lymphomagenesis.
SMDB: pivotal somatic sequence alterations reprogramming regulatory cascades
Authors: Jiang Limin , Duan Mingrui , Guo Fei , Tang Jijun , Oybamiji Olufunmilola , Yu Hui , Ness Scott , Zhao Ying-Yong , Mao Peng , Guo Yan 
Published: October 2020

Abstract
Binding motifs for transcription factors, RNA-binding proteins, microRNAs (miRNAs), etc. are vital for proper gene transcription and translation regulation. Sequence alteration mechanisms including single nucleotide mutations, insertion, deletion, RNA editing and single nucleotide polymorphism can lead to gains and losses of binding motifs; such consequentially emerged or vanished binding motifs are termed ‘somatic motifs’ by us. Somatic motifs have been studied sporadically but have never been curated into a comprehensive resource. By analyzing various types of sequence altering data from large consortiums, we successfully identified millions of somatic motifs, including those for important transcription factors, RNA-binding proteins, miRNA seeds and miRNA–mRNA 3′-UTR target motifs. While a few of these somatic motifs have been well studied, our results contain many novel somatic motifs that occur at high frequency and are thus likely to cause important biological repercussions. Genes targeted by these altered motifs are excellent candidates for further mechanism studies. Here, we present the first database that hosts millions of somatic motifs ascribed to a variety of sequence alteration mechanisms.
AI-Driver: an ensemble method for identifying driver mutations in personal cancer genomes
Authors: Wang Haoxuan , Wang Tao , Zhao Xiaolu , Wu Honghu , You Mingcong , Sun Zhongsheng , Mao Fengbiao 
Published: October 2020

AbstractThe current challenge in cancer research is to increase the resolution of driver prediction from gene-level to mutation-level, which is more closely aligned with the goal of precision cancer medicine. Improved methods to distinguish drivers from passengers are urgently needed to dig out driver mutations from increasing exome sequencing studies. Here, we developed an ensemble method, AI-Driver (AI-based driver classifier, https://github.com/hatchetProject/AI-Driver), to predict the driver status of somatic missense mutations based on 23 pathogenicity features. AI-Driver has the best overall performance compared with any individual tool and two cancer-specific driver predicting methods. We demonstrate the superior and stable performance of our model using four independent benchmarks. We provide pre-computed AI-Driver scores for all possible human missense variants (http://aidriver.maolab.org/) to identify driver mutations in the sea of somatic mutations discovered by personal cancer sequencing. We believe that AI-Driver together with pre-computed database will play vital important roles in the human cancer studies, such as identification of driver mutation in personal cancer genomes, discovery of targeting sites for cancer therapeutic treatments and prediction of tumor biomarkers for early diagnosis by liquid biopsy.
Serum bicarbonate is associated with kidney outcomes in autosomal dominant polycystic kidney disease
Authors: Blijdorp Charles J , Severs David , Musterd-Bhaggoe Usha M , Gansevoort Ronald T , Zietse Robert , Hoorn Ewout J ,   DIPAK Consortium, Drenth Joost P H , de Fijter Johannes W , Losekoot Monique , Meijer Esther , Peters Dorien J M , Visser Folkert W , Wetzels Jacques F 
Published: October 2020

Abstract

Background
Metabolic acidosis accelerates progression of chronic kidney disease, but whether this is also true for autosomal dominant polycystic kidney disease (ADPKD) is unknown.

Methods
Patients with ADPKD from the DIPAK (Developing Interventions to halt Progression of ADPKD) trial were included [n = 296, estimated glomerular filtration rate (eGFR) 50 ± 11 mL/min/1.73 m2, 2.5 years follow-up]. Outcomes were worsening kidney function (30% decrease in eGFR or kidney failure), annual eGFR change and height-adjusted total kidney and liver volumes (htTKV and htTLV). Cox and linear regressions were adjusted for prognostic markers for ADPKD [Mayo image class and predicting renal outcomes in ADPKD (PROPKD) scores] and acid–base parameters (urinary ammonium excretion).

Results
Patients in the lowest tertile of baseline serum bicarbonate (23.1 ± 1.6 mmol/L) had a significantly greater risk of worsening kidney function [hazard ratio = 2.95, 95% confidence interval (CI) 1.21–7.19] compared with patients in the highest tertile (serum bicarbonate 29.0 ± 1.3 mmol/L). Each mmol/L decrease in serum bicarbonate increased the risk of worsening kidney function by 21% in the fully adjusted model (hazard ratio = 1.21, 95% CI 1.06–1.37). Each mmol/L decrease of serum bicarbonate was also associated with further eGFR decline (−0.12 mL/min/1.73 m2/year, 95% CI −0.20 to −0.03). Serum bicarbonate was not associated with changes in htTKV or htTLV growth.

Conclusions
In patients with ADPKD, a lower serum bicarbonate within the normal range predicts worse kidney outcomes independent of established prognostic factors for ADPKD and independent of urine ammonium excretion. Serum bicarbonate may add to prognostic models and should be explored as a treatment target in ADPKD.
HER2-targeted therapy prolongs survival in patients with HER2-positive breast cancer and intracranial metastatic disease: a systematic review and meta-analysis
Authors: Erickson Anders W , Ghodrati Farinaz , Habbous Steven , Jerzak Katarzyna J , Sahgal Arjun , Ahluwalia Manmeet S , Das Sunit 
Published: October 2020

AbstractBackgroundIntracranial metastatic disease (IMD) is a serious and known complication of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The role of targeted therapy for patients with HER2-positive breast cancer and IMD remains unclear. In this study, we sought to evaluate the effect of HER2-targeted therapy on IMD from HER2-positive breast cancer.MethodsWe searched MEDLINE, EMBASE, CENTRAL, and gray literature sources for interventional and observational studies reporting survival, response, and safety outcomes for patients with IMD receiving HER2-targeted therapy. We pooled outcomes through meta-analysis and examined confounder effects through forest plot stratification and meta-regression. Evidence quality was evaluated using GRADE (PROSPERO CRD42020161209).ResultsA total of 97 studies (37 interventional and 60 observational) were included. HER2-targeted therapy was associated with prolonged overall survival (hazard ratio [HR] 0.47; 95% confidence interval [CI], 0.39–0.56) without significantly prolonged progression-free survival (HR 0.52; 95% CI, 0.27–1.02) versus non-targeted therapy; the intracranial objective response rate was 19% (95% CI, 12–27%), intracranial disease control rate 62% (95% CI, 55–69%), intracranial complete response rate 0% (95% CI, 0–0.01%), and grade 3+ adverse event rate 26% (95% CI, 11–45%). Risk of bias was high in 40% (39/97) of studies.ConclusionThese findings support a potential role for systemic HER2-targeted therapy in the treatment of patients with IMD from HER2-positive metastatic breast cancer.
Time-resolved spectroscopy and photometry of M dwarf flare star YZ Canis Minoris with OISTER and TESS: Blue asymmetry in the Hα line during the non-white light flare
Authors: Maehara Hiroyuki , Notsu Yuta , Namekata Kousuke , Honda Satoshi , Kowalski Adam F , Katoh Noriyuki , Ohshima Tomohito , Iida Kota , Oeda Motoki , Murata Katsuhiro L , Yamanaka Masayuki , Takagi Kengo , Sasada Mahito , Akitaya Hiroshi , Ikuta Kai , Okamoto Soshi , Nogami Daisaku , Shibata Kazunari 
Published: October 2020

AbstractIn this paper, we present the results from spectroscopic and photometric observations of the M-type flare star YZ CMi in the framework of the Optical and Infrared Synergetic Telescopes for Education and Research (OISTER) collaborations during the Transiting Exoplanet Survey Satellite (TESS) observation period. We detected 145 white-light flares from the TESS light-curve and four Hα flares from the OISTER observations performed between 2019 January 16 and 18. Among them, three Hα flares were associated with white-light flares. However, one of them did not show clear brightening in the continuum; during this flare, the Hα line exhibited blue asymmetry which lasted for ∼60 min. The line-of-sight velocity of the blueshifted component is in the range from −80 to −100 km s−1. This suggests that there can be upward flows of chromospheric cool plasma even without detectable red/near-infrared (NIR) continuum brightening. By assuming that the blue asymmetry in the Hα line was caused by a prominence eruption on YZ CMi, we estimated the mass and kinetic energy of the upward-moving material to be 1016–1018 g and 1029.5–1031.5 erg, respectively. The estimated mass is comparable to expectations from the empirical relation between the flare X-ray energy and mass of upward-moving material for stellar flares and solar coronal mass ejections (CMEs). In contrast, the estimated kinetic energy for the non-white-light flare on YZ CMi is roughly two orders of magnitude smaller than that expected from the relation between flare X-ray energy and kinetic energy for solar CMEs. This could be understood by the difference in the velocity between CMEs and prominence eruptions.
NATURAL RADIOACTIVITY OF THE CRYSTALLINE BASEMENT ROCKS OF THE PELORITANI MOUNTAINS (NORTH-EASTERN SICILY, ITALY): MEASUREMENTS AND RADIOLOGICAL HAZARD
Authors: Romano D , Caridi F , Di Bella M , Italiano F , Magazù S , Caccamo M T , Tripodo A , Faggio G , Grillo R , Triolo C , Messina G , Gattuso A , Sabatino G 
Published: October 2020

Abstract
Crystalline rocks can produce dangerous radiation levels on the basis of their content in radioisotopes. Here, we report radiological data from 10 metamorphic and igneous rock samples collected from the crystalline basement of the Peloritani Mountains (southern Italy). In order to evaluate the radiological properties of these rocks, the gamma radiation and the radon emanation have been measured. Moreover, since some of these rocks are employed as building materials, we assess the potential hazard for population connected to their use. Gamma spectroscopy was used to measure the 226Ra, 232Th and 40K activity concentration, whereas the radon emanation was investigated by using a RAD 7 detector. The results show 226Ra, 232Th and 40K activity concentration values ranging from (17 ± 4) to (56 ± 8) Bq kg−1, (14 ± 3) to (77 ± 14) Bq kg−1 and (167 ± 84) to (1760 ± 242) Bq kg−1, respectively. Values of the annual effective dose equivalent outdoor range from 0.035 to 0.152 mSv y−1, whereas the gamma index is in the range of 0.22–0.98. The 222Rn emanation coefficient and the 222Rn surface exhalation rate vary from (0.63 ± 0.3) to (8.27 ± 1.6)% and from (0.12 ± 0.03) to (2.75 ± 0.17) Bq m−2 h−1, respectively. The indoor radon derived from the building use of these rocks induces an approximate contribution to the annual effective dose ranging from 8 to 176 μSv y−1. All the obtained results suggest that the crystalline rocks from the Peloritani Mountains are not harmful for the residential population, even though they induce annual effective doses due to terrestrial gamma radiation above the worldwide average values. Moreover, their use as building materials does not produce significant health hazards connected to the indoor radon exposure.
Compounded Vulnerability: The Consequences of Immigration Detention for Institutional Attachment and System Avoidance in Mixed-Immigration-Status Families
Authors: Patler Caitlin , Gonzalez Gabriela 
Published: October 2020

AbstractWhile an extensive body of literature has analyzed the spillover and intergenerational consequences of mass incarceration, fewer studies explore the consequences of a parallel system: mass immigration detention. Every year, Immigration and Customs Enforcement imprisons hundreds of thousands of noncitizens as they await adjudication on their deportation proceedings, sometimes for months or years at a time. Many detained individuals have lived in the United States for decades and have spouses and/or dependent children that rely on them. This analysis brings together research on immigrant families, mass incarceration, and system avoidance to examine the spillover consequences of immigration detention. Using a multigenerational and multi-perspective research design, we analyze 104 interviews conducted in California with detained parents, non-detained spouses/partners, and their school-age children. Findings suggest that members of these mixed-status families may limit their engagement with surveilling institutions during a family member’s detention. These experiences are rooted in what we call compounded vulnerability—that is, both in the experience of parental/spousal confinement but also as members of mixed-immigration-status families facing the possibility of deportation.
Modular cell-free expression plasmids to accelerate biological design in cells
Authors: Karim Ashty S , Liew Fungmin (Eric) , Garg Shivani , Vögeli Bastian , Rasor Blake J , Gonnot Aislinn , Pavan Marilene , Juminaga Alex , Simpson Séan D , Köpke Michael , Jewett Michael C 
Published: October 2020

AbstractIndustrial biotechnology aims to produce high-value products from renewable resources. This can be challenging because model microorganisms—organisms that are easy to use like Escherichia coli—often lack the machinery required to utilize desired feedstocks like lignocellulosic biomass or syngas. Non-model organisms, such as Clostridium, are industrially proven and have desirable metabolic features but have several hurdles to mainstream use. Namely, these species grow more slowly than conventional laboratory microbes, and genetic tools for engineering them are far less prevalent. To address these hurdles for accelerating cellular design, cell-free synthetic biology has matured as an approach for characterizing non-model organisms and rapidly testing metabolic pathways in vitro. Unfortunately, cell-free systems can require specialized DNA architectures with minimal regulation that are not compatible with cellular expression. In this work, we develop a modular vector system that allows for T7 expression of desired enzymes for cell-free expression and direct Golden Gate assembly into Clostridium expression vectors. Utilizing the Joint Genome Institute’s DNA Synthesis Community Science Program, we designed and synthesized these plasmids and genes required for our projects allowing us to shuttle DNA easily between our in vitro and in vivo experiments. We next validated that these vectors were sufficient for cell-free expression of functional enzymes, performing on par with the previous state-of-the-art. Lastly, we demonstrated automated six-part DNA assemblies for Clostridium autoethanogenum expression with efficiencies ranging from 68% to 90%. We anticipate this system of plasmids will enable a framework for facile testing of biosynthetic pathways in vitro and in vivo by shortening development cycles.
Gestational Cd Exposure in the CD-1 Mouse Induces Sex-Specific Hepatic Insulin Insensitivity, Obesity, and Metabolic Syndrome in Adult Female Offspring
Authors: Jackson Thomas W , Ryherd Garret L , Scheibly Chris M , Sasser Aubrey L , Guillette T C , Belcher Scott M 
Published: October 2020

AbstractThere is compelling evidence that developmental exposure to toxic metals increases risk for obesity and obesity-related morbidity including cardiovascular disease and type 2 diabetes. To explore the hypothesis that developmental Cd exposure increases risk of obesity later in life, male, and female CD-1 mice were maternally exposed to 500 ppb CdCl2 in drinking water during a human gestational equivalent period (gestational day 0-postnatal day 10 [GD0-PND10]). Hallmark indicators of metabolic disruption, hepatic steatosis, and metabolic syndrome were evaluated prior to birth through adulthood. Maternal blood Cd levels were similar to those observed in human pregnancy cohorts, and Cd was undetected in adult offspring. There were no observed impacts of exposure on dams or pregnancy-related outcomes. Results of glucose and insulin tolerance testing revealed that Cd exposure impaired offspring glucose homeostasis on PND42. Exposure-related increases in circulating triglycerides and hepatic steatosis were apparent only in females. By PND120, Cd-exposed females were 30% heavier with 700% more perigonadal fat than unexposed control females. There was no evidence of dyslipidemia, steatosis, increased weight gain, nor increased adiposity in Cd-exposed male offspring. Hepatic transcriptome analysis on PND1, PND21, and PND42 revealed evidence for female-specific increases in oxidative stress and mitochondrial dysfunction with significant early disruption of retinoic acid signaling and altered insulin receptor signaling consistent with hepatic insulin sensitivity in adult females. The observed steatosis and metabolic syndrome-like phenotypes resulting from exposure to 500 ppb CdCl2 during the pre- and perinatal period of development equivalent to human gestation indicate that Cd acts developmentally as a sex-specific delayed obesogen.
Tobacco-Related Exposure Upregulates Circ_0035266 to Exacerbate Inflammatory Responses in Human Bronchial Epithelial Cells
Authors: Hua Qiuhan , Liu Yufei , Li Meizhen , Chen Yingnan , Diao Qinqin , Zeng Huixian , Jiang Yiguo 
Published: October 2020

Abstract
One of the most carcinogenic chemicals found in cigarette tobacco smoke is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which has been confirmed to be associated with the etiology of diverse cancers. Lipopolysaccharide (LPS), another biologically active component of cigarette smoke, is a risk factor which enhances NNK-induced lung tumorigenesis due to chronic lung inflammation. Although inflammatory responses play critical roles in the initiation of many tumors, our knowledge about the mechanisms of NNK+LPS on inflammation is currently limited. Here, we investigated the inflammatory effects of NNK+LPS in human bronchial epithelial cells (BEAS-2B) and explored the underlying mechanisms mediated by circular RNAs (circRNAs). We identified a novel circRNA, circ_0035266, which was strongly upregulated in NNK+LPS-induced BEAS-2B cells and enhanced the inflammatory responses to NNK+LPS by regulating the secretion of pro-inflammatory cytokines interleukin (IL)-6 and IL-8. Specifically, circ_0035266 knockdown alleviated NNK+LPS-induced inflammatory responses, whereas overexpression of circ_0035266 had the opposite effect. Moreover, dual-luciferase reporter and fluorescence in situ hybridization (FISH) assays verified that circ_0035266 bound to miR-181d-5p directly in the cytoplasm. qRT-PCR, dual-luciferase reporter assays, and Western blot analyses showed that DDX3X (DDX3) was the downstream target of miR-181d-5p and that DDX3X expression levels were modulated by circ_0035266. These results suggested that circ_0035266 served as a competitive endogenous RNA for miR-181d-5p to regulate DDX3X expression, which is involved in the modulation of NNK+LPS-induced inflammatory responses in BEAS-2B cells.
The End - or a New Beginning? The EU/UK Withdrawal Agreement
Authors: Peers Steve 
Published: October 2020

Abstract
The Brexit withdrawal agreement is full of tensions between EU and international law, and mixes together provisions winding down the UK's membership and continuing the EU/UK relationship—culminating in the confused and incomplete provisions on Northern Ireland. This paper analyses the key elements of the agreement, including its legal effect, dispute settlement provisions, and rules on UK and EU citizens' acquired rights.
Sleeping with the enemy: unravelling the symbiotic relationships between the scale wormNeopolynoe chondrocladiae(Annelida: Polynoidae) and its carnivorous sponge hosts
Authors: Taboada Sergi , Serra Silva Ana , Díez-Vives Cristina , Neal Lenka , Cristobo Javier , Ríos Pilar , Hestetun Jon Thomassen , Clark Brett , Rossi Maria Eleonora , Junoy Juan , Navarro Joan , Riesgo Ana 
Published: October 2020

AbstractThe North Atlantic deep-water polynoid worm Neopolynoe chondrocladiae is involved in an exceptional symbiotic relationship with two hosts: the carnivorous sponges Chondrocladia robertballardi and Chondrocladia virgata. While this is an obligate symbiotic relationship, its real nature is unclear. We used a multidisciplinary approach to narrow down the type of symbiotic relationship between symbiont and hosts. Molecular connectivity analyses using COI and 16S suggest that N. chondrocladiae has high potential for dispersal, connecting sites hundreds of kilometres apart, likely aided by oceanographic currents. Microbial analyses on different anatomical parts of five Chondrocladia species suggest that the presence of the worm in C. robertballardi does not affect the microbiome of the sponge. MicroCT analysis on N. chondrocladiae show that it has dorsally oriented parapodia, which might prevent the worm from getting trapped in the sponge. A faecal pellet recovered from the worm suggests that the polynoid feeds on the crustacean prey captured by the sponge, something corroborated by our stable isotope analysis. Light and confocal microscopy images suggest that N. chondrocladiae elytra produce bioluminescence. We propose that the worm might use bioluminescence as a lure for prey (increasing the food available for both the sponge and the polynoid) and thus fuelling a mutualistic relationship.