bluuebunny/crossref_metadata_2025 huggingface dataset:
A map of tumor–host interactions in glioma at single-cell resolution
Authors: Caruso Francesca Pia , Garofano Luciano , D'Angelo Fulvio , Yu Kai , Tang Fuchou , Yuan Jinzhou , Zhang Jing , Cerulo Luigi , Pagnotta Stefano M , Bedognetti Davide , Sims Peter A , Suvà Mario , Su Xiao-Dong , Lasorella Anna , Iavarone Antonio , Ceccarelli Michele
Published: October 2020

Background

Single-cell RNA sequencing is the reference technique for characterizing the heterogeneity of the tumor microenvironment. The composition of the various cell types making up the microenvironment can significantly affect the way in which the immune system activates cancer rejection mechanisms. Understanding the cross-talk signals between immune cells and cancer cells is of fundamental importance for the identification of immuno-oncology therapeutic targets.

Results

We present a novel method, single-cell Tumor–Host Interaction tool (scTHI), to identify significantly activated ligand–receptor interactions across clusters of cells from single-cell RNA sequencing data. We apply our approach to uncover the ligand–receptor interactions in glioma using 6 publicly available human glioma datasets encompassing 57,060 gene expression profiles from 71 patients. By leveraging this large-scale collection we show that unexpected cross-talk partners are highly conserved across different datasets in the majority of the tumor samples. This suggests that shared cross-talk mechanisms exist in glioma.

Conclusions

Our results provide a complete map of the active tumor–host interaction pairs in glioma that can be therapeutically exploited to reduce the immunosuppressive action of the microenvironment in brain tumor.
Complete phenomenon of reflection at the plane boundary of a dissipative anisotropic elastic medium
Authors: Sharma M D , Nain Suman
Published: October 2020

A complex slowness vector governs the 3-D propagation of harmonic plane waves in a dissipative elastic medium with general anisotropy. In any sagittal plane, this dual vector is specified with phase direction, propagation velocity and coefficients for attenuation. A generalized reflection phenomenon is illustrated for incidence of inhomogeneous waves at the stress free boundary of the medium. Each reflected wave at the boundary is characterized by its propagation direction, propagation velocity, inhomogeneity, amplitude ratio, phase shift and energy flux. These propagation characteristics are exhibited graphically for a numerical example of anisotropic viscoelastic medium.
Prawns, justice, and relationships of care in Stilbaai, South Africa
Authors: Norton Marieke
Published: October 2020

This story is concerned with the intersection of governance, stewardship, care taking, and extraction. It is centred on insights gained through repeated encounters with bait prawns during 7 years of fieldwork in Stilbaai, South Africa. These prawns are intended as angling bait, but they are entangled in a host of complications—or relations—the discovery of which eventually led me see them differently than before. More recently, I have looked into the role of marine protected areas in the everyday lives of residents, researching conservation management in Stilbaai in connection with the Southern Cape Interdisciplinary Fisheries Research project. In that work, I use the idea of relationality, as understood from an anthropological perspective, to speak about what long-term stewardship needs to take into account. Understanding more about the mudprawn and where it lives in the ecosystem, how people extract it, what it is used for, and how it is thought of has provided an access point for me into thinking about coastal social–ecological systems and how to communicate their needs. In this story, I reflect on these creatures as they live in my research, showing what this species can teach about coastal sustainability more generically.
Evaluation of 3 SARS-CoV-2 IgG Antibody Assays and Correlation with Neutralizing Antibodies
Authors: Rychert Jenna , Couturier Marc Roger , Elgort Marc , Lozier Bucky Ken , La’ulu Sonia , Genzen Jonathan R , Straseski Joely A , Delgado Julio C , Slev Patricia R
Published: October 2020

Background

As serologic assays for SARS-CoV-2 become more widely utilized, it is important to understand their performance characteristics and correlation with neutralizing antibodies. We evaluated 3 commonly used SARS-CoV-2 IgG assays (Abbott, DiaSorin, and EUROIMMUN) for clinical sensitivity, specificity, and correlation with neutralizing antibodies, and then compared antibody kinetics during the acute phase of infection.

Methods

Three panels of samples were tested on every assay. Sensitivity was assessed using a panel of 35 specimens serially collected from 7 patients with RT–PCR-confirmed COVID-19. Specificity was determined using 100 sera samples collected in 2018 from healthy individuals prior to the outbreak. Analytical specificity was determined using a panel of 37 samples from individuals with respiratory illnesses other than COVID-19.

Results

Clinical sensitivity was 91.43% (95% CI 76.94–98.20%) for Abbott, and 88.57% (95% CI 73.26–96.80%) for both DiaSorin and EUROIMMUN. Clinical specificity was 99.00% (95% CI 94.55–99.97%) for Abbott and DiaSorin and 94.00% (95% CI 87.40–97.77%) for EUROIMMUN. The IgG assays demonstrated good qualitative agreement (minimum of 94%) and good correlation between the quantitative result for each combination of assays (r2 ≥ 0.90). The neutralizing antibody response did not necessarily follow the same temporal kinetics as the IgG response and did not necessarily correlate with IgG values.

Conclusion

The 3 IgG antibody assays demonstrated comparable performance characteristics. Importantly, a qualitative positive IgG result obtained with any of the assays was associated with the presence of neutralizing antibodies; however, neutralizing antibody concentrations did not correlate well with signal to cutoff ratios.
Key components and IT assistance of participant management in clinical research: a scoping review
Authors: Pung Johannes , Rienhoff Otto
Published: October 2020

Objectives

Managing participants and their data are fundamental for the success of a clinical trial. Our review identifies and describes processes that deal with management of trial participants and highlights information technology (IT) assistance for clinical research in the context of participant management.

Methods

A scoping literature review design, based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement, was used to identify literature on trial participant-related proceedings, work procedures, or workflows, and assisting electronic systems.

Results

The literature search identified 1329 articles of which 111 were included for analysis. Participant-related procedures were categorized into 4 major trial processes: recruitment, obtaining informed consent, managing identities, and managing administrative data. Our results demonstrated that management of trial participants is considered in nearly every step of clinical trials, and that IT was successfully introduced to all participant-related areas of a clinical trial to facilitate processes.

Discussion

There is no precise definition of participant management, so a broad search strategy was necessary, resulting in a high number of articles that had to be excluded. Nevertheless, this review provides a comprehensive overview of participant management-related components, which was lacking so far. The review contributes to a better understanding of how computer-assisted management of participants in clinical trials is possible.
Is the Water Supply a Key Factor in Stingless Bees’ Intoxication?
Authors: Rosa-Fontana Annelise de Souza , Dorigo Adna Suelen , Soares-Lima Hellen Maria , Nocelli Roberta Cornélio Ferreira , Malaspina Osmar
Published: October 2020

Water is an important resource for stingless bees, serving for both honey dilution and the composition of larval food inside nests, yet can be an important route of exposure to pesticides. Assuming bees can forage naturally on pesticide-contaminated or noncontaminated areas, we investigated whether water supply influences the choice between neonicotinoid-dosed or nondosed feeders and on mortality of the stingless bee, Melipona scutellaris (Latreille, Hymenoptera, Apidae). At the field concentration, there was no significant mortality; however, the bees were not able to distinguish the feeders. In the cages containing high-concentration feeders, with water supply, the bees preferred nondosed food, and with no water, the mortality increased. Considering that in the field it is common to find extrapolated concentrations, our work suggested that water may allow avoidance of high dosed food and minimize mortality.
Seasonal Activity of Haemaphysalis longicornis (Acari: Ixodidae) in Southern New York State
Authors: Piedmonte Nicholas P , Vinci Vanessa C , Daniels Thomas J , Backenson Bryon P , Falco Richard C
Published: October 2020

The Asian longhorned tick, Haemaphysalis longicornis Neumann, is a species native to eastern Asia that has recently been discovered in the United States. In its native range, H. longicornis transmits pathogens that cause disease in humans and livestock. It is currently unknown whether H. longicornis will act as a vector in the United States. Understanding its seasonal activity patterns will be important in identifying which times of the year represent greatest potential risk to humans and livestock should this species become a threat to animal or public health. A study site was established in Yonkers, NY near the residence associated with the first reported human bite from H. longicornis in the United States. Ticks were collected once each week from July 2018 to November 2019. Haemaphysalis longicornis larvae were most active from August to November, nymphs from April to July, and adult females from June to September. This pattern of activity suggests that H. longicornis is capable of completing a generation within a single year and matches the patterns observed in its other ranges in the northern hemisphere. The data presented here contribute to a growing database for H. longicornis phenology in the northeastern United States. Potential implications of the short life cycle for the tick’s vectorial capacity are discussed.
Pilot Trial of a Sleep-Promoting Intervention for Children With Type 1 Diabetes
Authors: Jaser Sarah S , Bergner Erin M , Hamburger Emily R , Bhatia Shivani , Lyttle Morgan , Bell Grace E , Slaughter J Christopher , Malow Beth A , Simmons Jill H
Published: October 2020

Objective

To assess the feasibility and acceptability of an educational sleep-promoting intervention (Sleep Coach Jr.) for school-aged children (ages 5–9) with type 1 diabetes (T1D) and their parents.

Methods

Parents and children (N = 39 dyads, mean child age = 8 years, 64% girls,) were randomized to either the Sleep Coach Jr. intervention, consisting of educational materials and three individual phone calls (N = 20), or the Standard Care condition (N = 19). Data were collected at enrollment and 3 months later. Children and parents wore actigraphy devices to obtain an objective measure of sleep characteristics, and parents completed questionnaire measures of sleep quality and psychosocial outcomes. Clinical data (i.e., hemoglobin A1c, glucose data) were obtained from children’s medical records.

Results

Feasibility and acceptability of the study were demonstrated to be high; all three sessions were completed by 80% of parents randomized to the Sleep Coach Jr. intervention, and 90% of parents completed follow-up data at 3 months. Parents reported high levels of satisfaction with the study and identified barriers to participation. No changes were observed in children’s sleep or diabetes outcomes, but parental sleep quality and well-being improved.

Conclusions

A brief, behavioral sleep-promoting intervention is feasible and acceptable for school-aged children with T1D and their parents. A larger trial is needed to evaluate efficacy of the intervention.
Setting Operator overhead charges in joint ventures: benchmarking legal agreements
Authors: Fernandes D'Costa Lois
Published: October 2020

Operators of extractive joint ventures are typically reimbursed for their costs incurred on a ‘no gain, no loss’ basis. Some costs can be directly attributed, but many corporate overhead charges are indirect and recovered through a negotiated overhead charge. These overhead charges are a recurring source of audit disputes, and can escalate to a point of delaying the approval of proposed budgets. Recent benchmarking of contractual language related to overhead charges across 76 joint ventures shows wide variety in both median rates as well as allowable costs included in overhead. Analysis also identified certain gaps in contractual agreements that likely give rise to overhead-related disputes, which leads to three ways for co-venturers to rethink their approach to setting, modifying, and auditing overhead charges – with an eye towards reducing the incidence of frictions and dispute.
A Qualitative Examination of Factors That Influence Sleep Among Shipboard Sailors
Authors: Schmied Emily A , Harrison Elizabeth M , Dell’Acqua Renee G , Perez Vanessa G , Glickman Gena , Hurtado Suzanne L
Published: October 2020

Introduction

Sleep disturbance is prevalent among service members; however, little is known about factors that compromise sleep in unique operational environments, such as naval ships. Given the importance of sleep to health and performance, it is critical to identify both causes and potential solutions to this serious issue. The objective of this qualitative study was to elucidate the barriers to sleep and the strategies service members use to improve their sleep and combat fatigue while living and working aboard ships (i.e., underway).

Methods and Materials

Interviews were conducted with 22 active duty service members assigned to sea duty. The semi-structured interview guide assessed the experiences of service members sleeping in shipboard environments. Interview transcripts were analyzed using applied thematic content analysis by two independent coders.

Results

Participants were largely male (77.8%) and enlisted (88.9%). The most common barrier to obtaining sufficient sleep was stress, followed by rotating schedules, and environmental factors (e.g., noise and light). Additionally, many participants reported prioritizing other activities over sleep when off duty. Many participants did not report using any specific strategies to improve their sleep while underway. Among those who did, most described mitigating environmental barriers (e.g., noise-cancelling headphones or sleep masks). However, some participants also acknowledged these strategies are not always feasible, either attributable to cost or because sailors must be able to respond to alarms or commands. Notably, few sailors reported using stress mitigation or relaxation strategies to help sleep. Ingesting caffeine was the only strategy sailors reported using to alert themselves while fatigued.

Conclusions

Service members reported many unique barriers to sleep in the shipboard environment, yet many did not report the use of strategies to mitigate them. Further, few used alerting techniques when fatigued. This at-risk population could benefit from targeted educational interventions on sleep-promoting behaviors, prioritization of sleep, and fatigue mitigation.
Stellar and weak lensing profiles of massive galaxies in the Hyper-Suprime Cam survey and in hydrodynamic simulations
Authors: Ardila Felipe , Huang Song , Leauthaud Alexie , Diemer Benedikt , Pillepich Annalisa , Chowdhury Rajdipa , Fiacconi Davide , Greene Jenny , Hearin Andrew , Hernquist Lars , Madau Piero , Mayer Lucio , Peirani Sébastien , Xhakaj Enia
Published: October 2020

We perform a consistent comparison of the mass and mass profiles of massive (M⋆ > 1011.4 M⊙) central galaxies at z ∼ 0.4 from deep Hyper Suprime-Cam (HSC) observations and from the Illustris, TNG100, and Ponos simulations. Weak lensing measurements from HSC enable measurements at fixed halo mass and provide constraints on the strength and impact of feedback at different halo mass scales. We compare the stellar mass function (SMF) and the Stellar-to-Halo Mass Relation (SHMR) at various radii and show that the radius at which the comparison is performed is important. In general, Illustris and TNG100 display steeper values of α where $M_{\star } \propto M_{\rm vir}^{\alpha }$. These differences are more pronounced for Illustris than for TNG100 and in the inner rather than outer regions of galaxies. Differences in the inner regions may suggest that TNG100 is too efficient at quenching in situ star formation at Mvir ≃ 1013 M⊙ but not efficient enough at Mvir ≃ 1014 M⊙. The outer stellar masses are in excellent agreement with our observations at Mvir ≃ 1013 M⊙, but both Illustris and TNG100 display excess outer mass as Mvir ≃ 1014 M⊙ (by ∼0.25 and ∼0.12 dex, respectively). We argue that reducing stellar growth at early times in $M_\star \sim 10^{9-10} \, \mathrm{M}_{\odot }$ galaxies would help to prevent excess ex-situ growth at this mass scale. The Ponos simulations do not implement AGN feedback and display an excess mass of ∼0.5 dex at r < 30 kpc compared to HSC which is indicative of overcooling and excess star formation in the central regions. The comparison of the inner profiles of Ponos and HSC suggests that the physical scale over which the central AGN limits star formation is r ≲ 20 kpc. Joint comparisons between weak lensing and galaxy stellar profiles are a direct test of whether simulations build and deposit galaxy mass in the correct dark matter haloes and thereby provide powerful constraints on the physics of feedback and galaxy growth. Our galaxy and weak lensing profiles are publicly available to facilitate comparisons with other simulations.
Mice born to females with oocyte-specific deletion of mitofusin 2 have increased weight gain and impaired glucose homeostasis
Authors: Garcia Bruna M , Machado Thiago S , Carvalho Karen F , Nolasco Patrícia , Nociti Ricardo P , del Collado Maite , Capo Bianco Maria J D , Grejo Mateus P , Augusto Neto José Djaci , Sugiyama Fabrícia H C , Tostes Katiane , Pandey Anand K , Gonçalves Luciana M , Perecin Felipe , Meirelles Flávio V , Ferraz José Bento S , Vanzela Emerielle C , Boschero Antônio C , Guimarães Francisco E G , Abdulkader Fernando , Laurindo Francisco R M , Kowaltowski Alicia J , Chiaratti Marcos R
Published: October 2020

Offspring born to obese and diabetic mothers are prone to metabolic diseases, a phenotype that has been linked to mitochondrial dysfunction and endoplasmic reticulum (ER) stress in oocytes. In addition, metabolic diseases impact the architecture and function of mitochondria-ER contact sites (MERCs), changes which associate with mitofusin 2 (MFN2) repression in muscle, liver and hypothalamic neurons. MFN2 is a potent modulator of mitochondrial metabolism and insulin signaling, with a key role in mitochondrial dynamics and tethering with the ER. Here, we investigated whether offspring born to mice with MFN2-deficient oocytes are prone to obesity and diabetes. Deletion of Mfn2 in oocytes resulted in a profound transcriptomic change, with evidence of impaired mitochondrial and ER function. Moreover, offspring born to females with oocyte-specific deletion of Mfn2 presented increased weight gain and glucose intolerance. This abnormal phenotype was linked to decreased insulinemia and defective insulin signaling, but not mitochondrial and ER defects in offspring liver and skeletal muscle. In conclusion, this study suggests a link between disrupted mitochondrial/ER function in oocytes and increased risk of metabolic diseases in the progeny. Future studies should determine whether MERC architecture and function are altered in oocytes from obese females, which might contribute toward transgenerational transmission of metabolic diseases.
A role for LSH in facilitating DNA methylation by DNMT1 through enhancing UHRF1 chromatin association
Authors: Han Mengmeng , Li Jialun , Cao Yaqiang , Huang Yuanyong , Li Wen , Zhu Haijun , Zhao Qian , Han Jing-Dong Jackie , Wu Qihan , Li Jiwen , Feng Jing , Wong Jiemin
Published: October 2020

LSH, a SNF2 family DNA helicase, is a key regulator of DNA methylation in mammals. How LSH facilitates DNA methylation is not well defined. While previous studies with mouse embryonic stem cells (mESc) and fibroblasts (MEFs) derived from Lsh knockout mice have revealed a role of Lsh in de novo DNA methylation by Dnmt3a/3b, here we report that LSH contributes to DNA methylation in various cell lines primarily by promoting DNA methylation by DNMT1. We show that loss of LSH has a much bigger effect in DNA methylation than loss of DNMT3A and DNMT3B. Mechanistically, we demonstrate that LSH interacts with UHRF1 but not DNMT1 and facilitates UHRF1 chromatin association and UHRF1-catalyzed histone H3 ubiquitination in an ATPase activity-dependent manner, which in turn promotes DNMT1 recruitment to replication fork and DNA methylation. Notably, UHRF1 also enhances LSH association with the replication fork. Thus, our study identifies LSH as an essential factor for DNA methylation by DNMT1 and provides novel insight into how a feed-forward loop between LSH and UHRF1 facilitates DNMT1-mediated maintenance of DNA methylation in chromatin.
Acetylation-modulated communication between the H3 N-terminal tail domain and the intrinsically disordered H1 C-terminal domain
Authors: Hao Fanfan , Murphy Kevin J , Kujirai Tomoya , Kamo Naoki , Kato Junko , Koyama Masako , Okamato Akimitsu , Hayashi Gosuke , Kurumizaka Hitoshi , Hayes Jeffrey J
Published: October 2020

Linker histones (H1s) are key structural components of the chromatin of higher eukaryotes. However, the mechanisms by which the intrinsically disordered linker histone carboxy-terminal domain (H1 CTD) influences chromatin structure and gene regulation remain unclear. We previously demonstrated that the CTD of H1.0 undergoes a significant condensation (reduction of end-to-end distance) upon binding to nucleosomes, consistent with a transition to an ordered structure or ensemble of structures. Here, we show that deletion of the H3 N-terminal tail or the installation of acetylation mimics or bona fide acetylation within H3 N-terminal tail alters the condensation of the nucleosome-bound H1 CTD. Additionally, we present evidence that the H3 N-tail influences H1 CTD condensation through direct protein-protein interaction, rather than alterations in linker DNA trajectory. These results support an emerging hypothesis wherein the H1 CTD serves as a nexus for signaling in the nucleosome.
TCRD and Pharos 2021: mining the human proteome for disease biology
Authors: Sheils Timothy K , Mathias Stephen L , Kelleher Keith J , Siramshetty Vishal B , Nguyen Dac-Trung , Bologa Cristian G , Jensen Lars Juhl , Vidović Dušica , Koleti Amar , Schürer Stephan C , Waller Anna , Yang Jeremy J , Holmes Jayme , Bocci Giovanni , Southall Noel , Dharkar Poorva , Mathé Ewy , Simeonov Anton , Oprea Tudor I
Published: October 2020

In 2014, the National Institutes of Health (NIH) initiated the Illuminating the Druggable Genome (IDG) program to identify and improve our understanding of poorly characterized proteins that can potentially be modulated using small molecules or biologics. Two resources produced from these efforts are: The Target Central Resource Database (TCRD) (http://juniper.health.unm.edu/tcrd/) and Pharos (https://pharos.nih.gov/), a web interface to browse the TCRD. The ultimate goal of these resources is to highlight and facilitate research into currently understudied proteins, by aggregating a multitude of data sources, and ranking targets based on the amount of data available, and presenting data in machine learning ready format. Since the 2017 release, both TCRD and Pharos have produced two major releases, which have incorporated or expanded an additional 25 data sources. Recently incorporated data types include human and viral-human protein–protein interactions, protein–disease and protein–phenotype associations, and drug-induced gene signatures, among others. These aggregated data have enabled us to generate new visualizations and content sections in Pharos, in order to empower users to find new areas of study in the druggable genome.
DrugCentral 2021 supports drug discovery and repositioning
Authors: Avram Sorin , Bologa Cristian G , Holmes Jayme , Bocci Giovanni , Wilson Thomas B , Nguyen Dac-Trung , Curpan Ramona , Halip Liliana , Bora Alina , Yang Jeremy J , Knockel Jeffrey , Sirimulla Suman , Ursu Oleg , Oprea Tudor I
Published: October 2020

DrugCentral is a public resource (http://drugcentral.org) that serves the scientific community by providing up-to-date drug information, as described in previous papers. The current release includes 109 newly approved (October 2018 through March 2020) active pharmaceutical ingredients in the US, Europe, Japan and other countries; and two molecular entities (e.g. mefuparib) of interest for COVID19. New additions include a set of pharmacokinetic properties for ∼1000 drugs, and a sex-based separation of side effects, processed from FAERS (FDA Adverse Event Reporting System); as well as a drug repositioning prioritization scheme based on the market availability and intellectual property rights forFDA approved drugs. In the context of the COVID19 pandemic, we also incorporated REDIAL-2020, a machine learning platform that estimates anti-SARS-CoV-2 activities, as well as the ‘drugs in news’ feature offers a brief enumeration of the most interesting drugs at the present moment. The full database dump and data files are available for download from the DrugCentral web portal.
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

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

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

The 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

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

Background

Intracranial 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.

Methods

We 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).

Results

A 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.

Conclusion

These 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

In 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

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

While 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

Industrial 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

There 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

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

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.