bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aviation policy instrument choice in Europe: high flying and crash landing? Understanding policy evolutions in the Netherlands and Germany
Authors: Berker Lars E. , Böcher Michael 
Published: April 2022

AbstractIn the public debate on climate change in Europe, aviation transport has become a bone of contention and thus also a target of political regulation. While the actual available policy instruments, their designs and effects have been extensively studied, their political economy has remained a rather blind spot of research. Therefore, in this article we explore factors accounting for the instrument choice in aviation policy. Revealing most different evolutions in this matter, the Netherlands and Germany represent appropriately illustrative cases for a comparative exploration. Based on the Political Process-inherent Dynamics Approach, we shed light on a highly complex and limiting institutional environment for aviation policy-making and ultimately identify diverging conceptions of problem structures as well as different configurations of party competition as main explanatory factors for instrument choice and aviation policy evolution.
(Trans)National Fairy Tale and Romantic Childhood: Humperdinck'sHänsel und Gretelthrough its Parisian Reception
Authors: Coombes T. F. 
Published: April 2022

AbstractAround 1900, Engelbert Humperdinck and Adelheid Wette'sHänsel und Gretelwas one of the most widely performed operas in Europe. The critical discourse prompted by its Paris premiere provides an opportunity for exploring the political dynamics of nineteenth-century fairy tales and for elucidating the piece's considerable historical significance. Although Humperdinck's opera was a prime vehicle for perpetuating Franco-German cultural competition, a prominent strand of its Parisian reception emphasised transnational commonalities linking French and German cultural heritage – an emphasis facilitated by the fairy tale's nationalist ideologies. According to some Parisian critics, the opera's wildly successful representation of childhood explained its international success. Certainly,Hänsel und Gretelembodied an influential perception of childhood that also animated late nineteenth-century French literary and political spheres. In so doing, the opera also gave musical and dramatic shape to some highly restrictive aspects of the Romantic image of the divinely protected child.
Are all children treated equally? Psychiatric care and treatment receipt among migrant, descendant and majority Swedish children: a register-based study
Authors: Gubi Ester , Sjöqvist Hugo , Dalman Christina , Bäärnhielm Sofie , Hollander Anna-Clara 
Published: April 2022

Abstract

Aims
Underutilisation of mental health services among migrant youth has been demonstrated repeatedly, but little is known about potential discrepancies in terms of treatment receipt for those who do reach services. This study examines the type and level of care received among migrant children and descendants of migrants, particularly investigating disparities in treatment receipt given a specific diagnosis.

Methods
We used register data of the total population aged 6–17 years in Stockholm, followed from 2006 to 2015, comprising 444 196 individuals, categorised as refugees, non-refugee migrants, descendants of migrants and Swedish-born. To identify recommended treatments for specific diagnoses we used official clinical guidelines. We report logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) of diagnosis receipt, treatment provision and level of care where a diagnosis was first registered.

Results
Migrant children had a lower likelihood of receiving a wide range of psychiatric diagnoses, including mood disorder (OR 0.58; 95% CI 0.52–0.64), anxiety disorder (OR 0.62; 95% CI 0.57–69) and neurodevelopmental disorder (OR 0.59; 95% CI 0.55–0.63). Moreover, when these diagnoses were set, migrant children had a lower likelihood of receiving the recommended treatments for these conditions compared to the majority individuals with the same diagnosis (OR of receiving psychotherapy for anxiety disorder and depression: 0.71; 95% CI 0.62–0.95 and 0.50; 95% CI 0.33–0.75, respectively; OR for receiving ADHD-medication: 0.49; 95% CI 0.43–0.54).

Conclusions
Migrant children risk underdiagnosis of various mental health conditions, and, when reaching mental health services, risk not receiving the optimal care available.
Interannual Variability and Multiyear Trends of Sea Surface Salinity in the Amazon‐Orinoco Plume Region From Satellite Observations and an Ocean Reanalysis
Authors: Da Nguyen Dac , Foltz Gregory R. 
Published: April 2022

AbstractThe Amazon and Orinoco Rivers form the largest river system on Earth with wide‐reaching impacts on the biophysical climate of the region. Based on 11 years of satellite observations, here we show strong interannual variability of sea surface salinity (SSS) in the plume region that is about three times larger than in the surrounding region. This variability has been driven mainly by changes in horizontal advection of the plume with smaller contributions from precipitation, river discharge, and vertical mixing. Interannual variability of horizontal advection occurs mainly near the eastern boundary of the plume region and especially in the latitude range of the North Equatorial Countercurrent (3°–10°N). The North Atlantic Oscillation (NAO) and El Niño Southern Oscillation (ENSO) strongly modulate SSS in the plume region during the boreal spring‐summer (flood) and fall‐winter (dry) seasons, respectively, through their impacts on the tropical North Atlantic Ocean circulation. Overall, the NAO exerts a stronger influence on plume SSS than ENSO. The plume SSS also shows a significant upward trend during 2010–2016, corresponding to transitions of the NAO and ENSO from negative to positive phases. This was followed by a downward trend during 2017–2020 when both the NAO and ENSO decreased from their 2015–2016 peaks. These results show that year‐to‐year changes in the spatial mean SSS of the Amazon‐Orinoco plume are driven mainly by large‐scale climate forcings and their associated imprints on tropical Atlantic Ocean circulation and very little by changes in river outflow and associated rainfall over land.
Estimating Hydraulic Properties of the Shallow Subsurface Using the Groundwater Response to Earth and Atmospheric Tides: A Comparison With Pumping Tests
Authors: Valois Rémi , Rau Gabriel C. , Vouillamoz Jean‐Michel , Derode Benoit 
Published: April 2022

AbstractEstimating subsurface hydraulic properties using the groundwater (GW) response to Earth tides (ET) and atmospheric pressure is an alternative approach to pumping or slug tests (passive vs. active methods). Yet testing the applicability of models under different subsurface conditions and comparing results with traditional hydraulic methods are lacking. We first review the assumptions of analytical models used to evaluate the GW response to ET and their applicability in unconfined to confined conditions. Second, we develop a robust approach to select the right model based on amplitude and phase pattern of the diurnal and semi‐diurnal tides. Third, based on earlier works we develop an approach to derive the hydraulic conductivity of the screened interval using the GW response to atmospheric tides, here named “atmospheric slug test” (AST). We estimate transmissivity and storativity at three shallow aquifers in Cambodia and compare the results with subsurface properties derived from pumping tests (PT). Transmissivity values from AST and PT are in good agreement. However, we show that storativity values derived from ET show large discrepancies if borehole skin effects are ignored. Further, the GW response to ET exhibits a strong decay in amplitude with frequency while maintaining close to zero and positive phase shifts. When supplemented with the calculated transmissivity values, none of the analytical models was able to reproduce this frequency dependent behavior. Our work emphasizes the need for evaluating passive methods robustness under different subsurface conditions. Further work is required to understand the frequency dependent GW response to natural or artificial forces.
RNA therapy: rich history, various applications and unlimited future prospects
Authors: Kim Young-Kook 
Published: April 2022

AbstractRNA therapy refers to the treatment or prevention of diseases using RNA-based molecules. The recent advent of a series of effective messenger RNA-based vaccines in response to the COVID-19 pandemic has reignited research interest in RNA therapy. Based on the accumulated results of long-term research in the field of RNA therapy spanning several decades, therapeutic agents for various diseases are being rapidly developed. These therapeutics tend to target diseases that cannot be treated with other conventional drug groups, and several clinical studies are underway for a variety of RNA-based therapeutics against various incurable diseases. This review describes the history of several important discoveries in RNA biology and their impact on key developments in RNA therapy as well as the advantages of RNA therapy. In addition, it describes the action mechanisms and examples of drugs approved for RNA therapy. Finally, this review discusses methods for RNA drug delivery to target organs and cells. Given that RNA therapy is expected to advance and play an integral role in the development of novel therapeutic agents for human diseases in the future, this review is designed to offer an updated reference point for researchers in this field.
Catestatin selects for colonization of antimicrobial-resistant gut bacterial communities
Authors: González-Dávila Pamela , Schwalbe Markus , Danewalia Arpit , Dalile Boushra , Verbeke Kristin , Mahata Sushil K , El Aidy Sahar 
Published: April 2022

Abstract
The gut microbiota is in continuous interaction with the innermost layer of the gut, namely the epithelium. One of the various functions of the gut epithelium, is to keep the microbes at bay to avoid overstimulation of the underlying mucosa immune cells. To do so, the gut epithelia secrete a variety of antimicrobial peptides, such as chromogranin A (CgA) peptide catestatin (CST: hCgA352-372). As a defense mechanism, gut microbes have evolved antimicrobial resistance mechanisms to counteract the killing effect of the secreted peptides. To this end, we treated wild-type mice and CST knockout (CST-KO) mice (where only the 63 nucleotides encoding CST have been deleted) with CST for 15 consecutive days. CST treatment was associated with a shift in the diversity and composition of the microbiota in the CST-KO mice. This effect was less prominent in WT mice. Levels of the microbiota-produced short-chain fatty acids, in particular, butyrate and acetate were significantly increased in CST-treated CST-KO mice but not the WT group. Both CST-treated CST-KO and WT mice showed a significant increase in microbiota-harboring phosphoethanolamine transferase-encoding genes, which facilitate their antimicrobial resistance. Finally, we show that CST was degraded by Escherichia coli via an omptin-protease and that the abundance of this gene was significantly higher in metagenomic datasets collected from patients with Crohn’s disease but not with ulcerative colitis. Overall, this study illustrates how the endogenous antimicrobial peptide, CST, shapes the microbiota composition in the gut and primes further research to uncover the role of bacterial resistance to CST in disease states such as inflammatory bowel disease.
First-line trifluridine/tipiracil + bevacizumab in patients with unresectable metastatic colorectal cancer: final survival analysis in the TASCO1 study
Authors: Van Cutsem E. , Danielewicz I. , Saunders M. P. , Pfeiffer P. , Argilés G. , Borg C. , Glynne-Jones R. , Punt C. J. A. , Van de Wouw A. J. , Fedyanin M. , Stroyakovskiy D. , Kroening H. , Garcia-Alfonso P. , Wasan H. , Falcone A. , Fougeray R. , Egorov A. , Amellal N. , Moiseyenko V. 
Published: April 2022

Abstract
Background
Therapeutic options are limited in patients with unresectable metastatic colorectal cancer (mCRC) ineligible for intensive chemotherapy. The use of trifluridine/tipiracil plus bevacizumab (TT-B) in this setting was evaluated in the TASCO1 trial; here, we present the final overall survival (OS) results.

Methods
TASCO1 was an open-label, non-comparative phase II trial. Patients (n = 153) were randomised 1:1 to TT-B (trifluridine/tipiracil 35 mg/m2 orally twice daily on days 1–5 and 8–12, and bevacizumab intravenously 5 mg/kg on days 1 and 15 of each 28-day cycle) or capecitabine plus bevacizumab (C-B; capecitabine, 1250 mg/m2 orally twice daily on days 1–14 and bevacizumab 7.5 mg/kg intravenously on day 1 of each 21-day cycle). Final OS was analysed when all patients had either died or withdrawn from the study. Adjusted multivariate regression was used to investigate the effects of pre-specified variables on OS.

Results
At 1 September 2020, median OS was 22.3 months (95% CI: 18.0–23.7) with TT-B and 17.7 months (95% CI: 12.6–19.8) with C-B (adjusted HR 0.78; 95% CI: 0.55–1.10). No variables negatively affected OS with TT-B. Safety results were consistent with prior findings.

Conclusions
TT-B is a promising therapeutic regimen in mCRC patients ineligible for intensive chemotherapy.

Clinical trial information
NCT02743221 (clinicaltrials.gov)
Aberrant promoter methylation contributes to LRIG1 silencing in basal/triple-negative breast cancer
Authors: Umeh-Garcia Maxine , O’Geen Henriette , Simion Catalina , Gephart Melanie Hayden , Segal David J. , Sweeney Colleen A. 
Published: April 2022

Abstract
Background
LRIG1, the founding member of the LRIG (leucine-rich repeat and immunoglobulin-like domain) family of transmembrane proteins, is a negative regulator of receptor tyrosine kinases and a tumour suppressor. Decreased LRIG1 expression is consistently observed in cancer, across diverse tumour types, and is linked to poor patient prognosis. However, mechanisms by which LRIG1 is repressed are not fully understood. Silencing of LRIG1 through promoter CpG island methylation has been reported in colorectal and cervical cancer but studies in breast cancer remain limited.

Methods
In silico analysis of human breast cancer patient data were used to demonstrate a correlation between DNA methylation and LRIG1 silencing in basal/triple-negative breast cancer, and its impact on patient survival. LRIG1 gene expression, protein abundance, and methylation enrichment were examined by quantitative reverse-transcription PCR, immunoblotting, and methylation immunoprecipitation, respectively, in breast cancer cell lines in vitro. We examined the impact of global demethylation on LRIG1 expression and methylation enrichment using 5-aza-2’-deoxycytidine. We also examined the effects of targeted demethylation of the LRIG1 CpG island, and transcriptional activation of LRIG1 expression, using the RNA guided deadCas9 transactivation system.

Results
Across breast cancer subtypes, LRIG1 expression is lowest in the basal/triple-negative subtype so we investigated whether differential methylation may contribute to this. Indeed, we find that LRIG1 CpG island methylation is most prominent in basal/triple-negative cell lines and patient samples. Use of the global demethylating agent 5-aza-2’-deoxycytidine decreases methylation leading to increased LRIG1 transcript expression in basal/triple-negative cell lines, while having no effect on LRIG1 expression in luminal/ER-positive cell lines. Using a CRISPR/deadCas9 (dCas9)-based targeting approach, we demonstrate that TET1-mediated demethylation (Tet1-dCas9) along with VP64-mediated transcriptional activation (VP64-dCas9) at the CpG island, increased endogenous LRIG1 expression in basal/triple-negative breast cancer cells, without transcriptional upregulation at predicted off-target sites. Activation of LRIG1 by the dCas9 transactivation system significantly increased LRIG1 protein abundance, reduced site-specific methylation, and reduced cancer cell viability. Our findings suggest that CRISPR-mediated targeted activation may be a feasible way to restore LRIG1 expression in cancer.

Conclusions
Our study contributes novel insight into mechanisms which repress LRIG1 in triple-negative breast cancer and demonstrates for the first time that targeted de-repression of LRIG1 in cancer cells is possible. Understanding the epigenetic mechanisms associated with repression of tumour suppressor genes holds potential for the advancement of therapeutic approaches.
ROR activation by Nobiletin enhances antitumor efficacy via suppression of IκB/NF-κB signaling in triple-negative breast cancer
Authors: Kim Eunju , Kim Yoon-Jin , Ji Zhiwei , Kang Jin Muk , Wirianto Marvin , Paudel Keshav Raj , Smith Joshua A. , Ono Kaori , Kim Jin-Ah , Eckel-Mahan Kristin , Zhou Xiaobo , Lee Hyun Kyoung , Yoo Ji Young , Yoo Seung-Hee , Chen Zheng 
Published: April 2022

AbstractTriple-negative breast cancer (TNBC) is a heterogeneous disease characterized by poor response to standard therapies and therefore unfavorable clinical outcomes. Better understanding of TNBC and new therapeutic strategies are urgently needed. ROR nuclear receptors are multifunctional transcription factors with important roles in circadian pathways and other processes including immunity and tumorigenesis. Nobiletin (NOB) is a natural compound known to display anticancer effects, and our previous studies showed that NOB activates RORs to enhance circadian rhythms and promote physiological fitness in mice. Here, we identified several TNBC cell lines being sensitive to NOB, by itself or in combination. Cell and xenograft experiments showed that NOB significantly inhibited TNBC cell proliferation and motility in vitro and in vivo. ROR loss- and gain-of-function studies showed concordant effects of the NOB–ROR axis on MDA-MB-231 cell growth. Mechanistically, we found that NOB activates ROR binding to the ROR response elements (RRE) of the IκBα promoter, and NOB strongly inhibited p65 nuclear translocation. Consistent with transcriptomic analysis indicating cancer and NF-κB signaling as major pathways altered by NOB, p65-inducible expression abolished NOB effects, illustrating a requisite role of NF-κB suppression mediating the anti-TNBC effect of NOB. Finally, in vivo mouse xenograft studies showed that NOB enhanced the antitumor efficacy in mammary fat pad implanted TNBC, as a single agent or in combination with the chemotherapy agent Docetaxel. Together, our study highlights an anti-TNBC mechanism of ROR-NOB via suppression of NF-κB signaling, suggesting novel preventive and chemotherapeutic strategies against this devastating disease.
UHRF1 establishes crosstalk between somatic and germ cells in male reproduction
Authors: Wu Yanqing , Duan Peng , Wen Yujiao , Zhang Jin , Wang Xiaoli , Dong Juan , Zhao Qiang , Feng Shenglei , Lv Chunyu , Guo Yang , Namekawa Satoshi H. , Yuan Shuiqiao 
Published: April 2022

AbstractSertoli cells (SCs) support and nourish germ cells (GCs) through their crosstalk during spermatogenesis. However, the underlying epigenetic mechanism that ensures SCs’ functions in this process remains unclear. Here, we report that UHRF1, a critical epigenetic regulator, is mainly expressed in human and mouse pre-mature SCs, and is essential for establishing Sertoli-Germ cell crosstalk. SC-specific UHRF1 knockout mice exhibit complete sterility with Sertoli cell (SC) proliferation and differentiation aberrance, blood-testis barrier (BTB) disruption, and immature germ cell (GC) sloughing. RNA sequencing and Whole Genome Bisulfite Sequencing (WGBS) revealed that many extracellular matrix (ECM)-related genes (e.g., Timp1, Trf, and Spp1) appeared upregulated with the DNA hypomethylation status in UHRF1-deficient SCs. Strikingly, overexpression of Timp1, Trf, and Spp1 in SCs in vitro and in vivo could phenocopy the SC-specific UHRF1-deficient mice. Our data demonstrated that UHRF1 regulates the transcriptional program of ECM-related genes in SCs and establishes SC-GC crosstalk.
Astroblastomas exhibit radial glia stem cell lineages and differential expression of imprinted and X-inactivation escape genes
Authors: Lehman Norman L. , Spassky Nathalie , Sak Müge , Webb Amy , Zumbar Cory T. , Usubalieva Aisulu , Alkhateeb Khaled J. , McElroy Joseph P. , Maclean Kirsteen H. , Fadda Paolo , Liu Tom , Gangalapudi Vineela , Carver Jamie , Abdullaev Zied , Timmers Cynthia , Parker John R. , Pierson Christopher R. , Mobley Bret C. , Gokden Murat , Hattab Eyas M. , Parrett Timothy , Cooke Ralph X. , Lehman Trang D. , Costinean Stefan , Parwani Anil , Williams Brian J. , Jensen Randy L. , Aldape Kenneth , Mistry Akshitkumar M. 
Published: April 2022

AbstractAstroblastomas (ABs) are rare brain tumors of unknown origin. We performed an integrative genetic and epigenetic analysis of AB-like tumors. Here, we show that tumors traceable to neural stem/progenitor cells (radial glia) that emerge during early to later brain development occur in children and young adults, respectively. Tumors with MN1-BEND2 fusion appear to present exclusively in females and exhibit overexpression of genes expressed prior to 25 post-conception weeks (pcw), including genes enriched in early ventricular zone radial glia and ependymal tumors. Other, histologically classic ABs overexpress or harbor mutations of mitogen-activated protein kinase pathway genes, outer and truncated radial glia genes, and genes expressed after 25 pcw, including neuronal and astrocyte markers. Findings support that AB-like tumors arise in the context of epigenetic and genetic changes in neural progenitors. Selective gene fusion, variable imprinting and/or chromosome X-inactivation escape resulting in biallelic overexpression may contribute to female predominance of AB molecular subtypes.
Normalizing and denoising protein expression data from droplet-based single cell profiling
Authors: Mulè Matthew P. , Martins Andrew J. , Tsang John S. 
Published: April 2022

AbstractMultimodal single-cell profiling methods that measure protein expression with oligo-conjugated antibodies hold promise for comprehensive dissection of cellular heterogeneity, yet the resulting protein counts have substantial technical noise that can mask biological variations. Here we integrate experiments and computational analyses to reveal two major noise sources and develop a method called “dsb” (denoised and scaled by background) to normalize and denoise droplet-based protein expression data. We discover that protein-specific noise originates from unbound antibodies encapsulated during droplet generation; this noise can thus be accurately estimated and corrected by utilizing protein levels in empty droplets. We also find that isotype control antibodies and the background protein population average in each cell exhibit significant correlations across single cells, we thus use their shared variance to correct for cell-to-cell technical noise in each cell. We validate these findings by analyzing the performance of dsb in eight independent datasets spanning multiple technologies, including CITE-seq, ASAP-seq, and TEA-seq. Compared to existing normalization methods, our approach improves downstream analyses by better unmasking biologically meaningful cell populations. Our method is available as an open-source R package that interfaces easily with existing single cell software platforms such as Seurat, Bioconductor, and Scanpy and can be accessed at “dsb [https://cran.r-project.org/package=dsb]”.