bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrating Bayesian Groundwater Mixing Modeling With On‐Site Helium Analysis to Identify Unknown Water Sources
Authors: Popp Andrea L. , Scheidegger Andreas , Moeck Christian , Brennwald Matthias S. , Kipfer Rolf 
Published: December 2019

AbstractAnalyzing groundwater mixing ratios is crucial for many groundwater management tasks such as assessing sources of groundwater recharge and flow paths. However, estimating groundwater mixing ratios is affected by various uncertainties, which are related to analytical and measurement errors of tracers, the selection of end‐members, and finding the most suitable set of tracers. Although these uncertainties are well recognized, it is still not common practice to account for them. We address this issue by using a new set of tracers in combination with a Bayesian modeling approach, which explicitly considers the possibility of unknown end‐members while fully accounting for tracer uncertainties. We apply the Bayesian model we developed to a tracer set, which includes helium (4He) analyzed on site to determine mixing ratios in groundwater. Thereby, we identify an unknown end‐member that contributes up to 84 ± 9% to the water mixture observed at our study site. For the 4He analysis, we use a newly developed Gas Equilibrium Membrane Inlet Mass Spectrometer (GE‐MIMS), operated in the field. To test the reliability of on‐site 4He analysis, we compare results obtained with the GE‐MIMS to the conventional lab‐based method, which is comparatively expensive and labor intensive. Our work demonstrates that (i) tracer‐aided Bayesian mixing modeling can detect unknown water sources, thereby revealing valuable insights into the conceptual understanding of the groundwater system studied, and (ii) on‐site 4He analysis with the GE‐MIMS system is an accurate and reliable alternative to the lab‐based analysis.
STING signaling and host defense against microbial infection
Authors: Ahn Jeonghyun , Barber Glen N. 
Published: December 2019

AbstractThe first line of host defense against infectious agents involves activation of innate immune signaling pathways that recognize specific pathogen-associated molecular patterns (PAMPs). Key triggers of innate immune signaling are now known to include microbial-specific nucleic acid, which is rapidly detected in the cytosol of the cell. For example, RIG-I-like receptors (RLRs) have evolved to detect viral RNA species and to activate the production of host defense molecules and cytokines that stimulate adaptive immune responses. In addition, host defense countermeasures, including the production of type I interferons (IFNs), can also be triggered by microbial DNA from bacteria, viruses and perhaps parasites and are regulated by the cytosolic sensor, stimulator of interferon genes (STING). STING-dependent signaling is initiated by cyclic dinucleotides (CDNs) generated by intracellular bacteria following infection. CDNs can also be synthesized by a cellular synthase, cGAS, following interaction with invasive cytosolic self-DNA or microbial DNA species. The importance of STING signaling in host defense is evident since numerous pathogens have developed strategies to prevent STING function. Here, we review the relevance of STING-controlled innate immune signaling in host defense against pathogen invasion, including microbial endeavors to subvert this critical process.
Quantum expander for gravitational-wave observatories
Authors: Korobko Mikhail , Ma Yiqiu , Chen Yanbei , Schnabel Roman 
Published: December 2019

AbstractThe quantum uncertainty of laser light limits the sensitivity of gravitational-wave observatories. Over the past 30 years, techniques for squeezing the quantum uncertainty, as well as for enhancing gravitational-wave signals with optical resonators have been invented. Resonators, however, have finite linewidths, and the high signal frequencies that are produced during the highly scientifically interesting ring-down of astrophysical compact-binary mergers still cannot be resolved. Here, we propose a purely optical approach for expanding the detection bandwidth. It uses quantum uncertainty squeezing inside one of the optical resonators, compensating for the finite resonators’ linewidths while keeping the low-frequency sensitivity unchanged. This quantum expander is intended to enhance the sensitivity of future gravitational-wave detectors, and we suggest the use of this new tool in other cavity-enhanced metrological experiments.
CLDN6 promotes tumor progression through the YAP1-snail1 axis in gastric cancer
Authors: Yu Site , Zhang Yeqian , Li Qing , Zhang Zizhen , Zhao Gang , Xu Jia 
Published: December 2019

AbstractClaudin6 (CLDN6), a member of the tight junction family, is a molecule involved in intercellular adhesion, acting as a physical barrier that prevents solutes and water from freely passing through the extracellular space. CLDN6 has important biological functions, and its abnormal expression is associated with Hepatitis C infection. However, there is limited research regarding its role in gastric cancer. In this study, we found that the expression of CLDN6 mRNA and protein was upregulated in gastric cancer cell lines and tissues, which indicated poor prognosis. Both in vitro and in vivo experiments showed that abnormal CLDN6 expression was associated with enhanced proliferation and invasion abilities of gastric cancer. CLDN6 reduced the phosphorylation of LATS1/2 and YAP1 by interacting with LATS1/2 in the Hippo signaling pathway. Thus, CLDN6 affected the entry of YAP1 into the nucleus, causing changes in downstream target genes. Moreover, YAP1 interacted with snail1 to affect the process of EMT and enhanced the invasive ability of GC cells. Collectively, CLDN6 promoted the proliferation and invasive ability of gastric cancer by affecting YAP1 and YAP1-snail1 axis.
A large size-selective DNA nanopore with sensing applications
Authors: Thomsen Rasmus P. , Malle Mette Galsgaard , Okholm Anders Hauge , Krishnan Swati , Bohr Søren S.-R. , Sørensen Rasmus Schøler , Ries Oliver , Vogel Stefan , Simmel Friedrich C. , Hatzakis Nikos S. , Kjems Jørgen 
Published: December 2019

AbstractTransmembrane nanostructures like ion channels and transporters perform key biological functions by controlling flow of molecules across lipid bilayers. Much work has gone into engineering artificial nanopores and applications in selective gating of molecules, label-free detection/sensing of biomolecules and DNA sequencing have shown promise. Here, we use DNA origami to create a synthetic 9 nm wide DNA nanopore, controlled by programmable, lipidated flaps and equipped with a size-selective gating system for the translocation of macromolecules. Successful assembly and insertion of the nanopore into lipid bilayers are validated by transmission electron microscopy (TEM), while selective translocation of cargo and the pore mechanosensitivity are studied using optical methods, including single-molecule, total internal reflection fluorescence (TIRF) microscopy. Size-specific cargo translocation and oligonucleotide-triggered opening of the pore are demonstrated showing that the DNA nanopore can function as a real-time detection system for external signals, offering potential for a variety of highly parallelized sensing applications.
Detection of the 5p – 4f orbital crossing and its optical clock transition in Pr9+
Authors: Bekker H. , Borschevsky A. , Harman Z. , Keitel C. H. , Pfeifer T. , Schmidt P. O. , Crespo López-Urrutia J. R. , Berengut J. C. 
Published: December 2019

AbstractRecent theoretical works have proposed atomic clocks based on narrow optical transitions in highly charged ions. The most interesting candidates for searches of physics beyond the Standard Model are those which occur at rare orbital crossings where the shell structure of the periodic table is reordered. There are only three such crossings expected to be accessible in highly charged ions, and hitherto none have been observed as both experiment and theory have proven difficult. In this work we observe an orbital crossing in a system chosen to be tractable from both sides: Pr$${}^{9+}$$

9
+

. We present electron beam ion trap measurements of its spectra, including the inter-configuration lines that reveal the sought-after crossing. With state-of-the-art calculations we show that the proposed nHz-wide clock line has a very high sensitivity to variation of the fine-structure constant, $$\alpha$$
α
, and violation of local Lorentz invariance; and has extremely low sensitivity to external perturbations.
Selective small molecule PARG inhibitor causes replication fork stalling and cancer cell death
Authors: Houl Jerry H. , Ye Zu , Brosey Chris A. , Balapiti-Modarage Lakshitha P. F. , Namjoshi Sarita , Bacolla Albino , Laverty Daniel , Walker Brian L. , Pourfarjam Yasin , Warden Leslie S. , Babu Chinnam Naga , Moiani Davide , Stegeman Roderick A. , Chen Mei-Kuang , Hung Mien-Chie , Nagel Zachary D. , Ellenberger Tom , Kim In-Kwon , Jones Darin E. , Ahmed Zamal , Tainer John A. 
Published: December 2019

AbstractPoly(ADP-ribose)ylation (PARylation) by PAR polymerase 1 (PARP1) and PARylation removal by poly(ADP-ribose) glycohydrolase (PARG) critically regulate DNA damage responses; yet, conflicting reports obscure PARG biology and its impact on cancer cell resistance to PARP1 inhibitors. Here, we found that PARG expression is upregulated in many cancers. We employed chemical library screening to identify and optimize methylxanthine derivatives as selective bioavailable PARG inhibitors. Multiple crystal structures reveal how substituent positions on the methylxanthine core dictate binding modes and inducible-complementarity with a PARG-specific tyrosine clasp and arginine switch, supporting inhibitor specificity and a competitive inhibition mechanism. Cell-based assays show selective PARG inhibition and PARP1 hyperPARylation. Moreover, our PARG inhibitor sensitizes cells to radiation-induced DNA damage, suppresses replication fork progression and impedes cancer cell survival. In PARP inhibitor-resistant A172 glioblastoma cells, our PARG inhibitor shows comparable killing to Nedaplatin, providing further proof-of-concept that selectively inhibiting PARG can impair cancer cell survival.
DNA methylation directs microRNA biogenesis in mammalian cells
Authors: Glaich Ohad , Parikh Shivang , Bell Rachel E. , Mekahel Keren , Donyo Maya , Leader Yodfat , Shayevitch Ronna , Sheinboim Danna , Yannai Sivan , Hollander Dror , Melamed Ze’ev , Lev-Maor Galit , Ast Gil , Levy Carmit 
Published: December 2019

AbstractMicroRNA (miRNA) biogenesis initiates co-transcriptionally, but how the Microprocessor machinery pinpoints the locations of short precursor miRNA sequences within long flanking regions of the transcript is not known. Here we show that miRNA biogenesis depends on DNA methylation. When the regions flanking the miRNA coding sequence are highly methylated, the miRNAs are more highly expressed, have greater sequence conservation, and are more likely to drive cancer-related phenotypes than miRNAs encoded by unmethylated loci. We show that the removal of DNA methylation from miRNA loci leads to their downregulation. Further, we found that MeCP2 binding to methylated miRNA loci halts RNA polymerase II elongation, leading to enhanced processing of the primary miRNA by Drosha. Taken together, our data reveal that DNA methylation directly affects miRNA biogenesis.
BRCA1 intronic Alu elements drive gene rearrangements and PARP inhibitor resistance
Authors: Wang Yifan , Bernhardy Andrea J. , Nacson Joseph , Krais John J. , Tan Yin-Fei , Nicolas Emmanuelle , Radke Marc R. , Handorf Elizabeth , Llop-Guevara Alba , Balmaña Judith , Swisher Elizabeth M. , Serra Violeta , Peri Suraj , Johnson Neil 
Published: December 2019

AbstractBRCA1 mutant carcinomas are sensitive to PARP inhibitor (PARPi) therapy; however, resistance arises. BRCA1 BRCT domain mutant proteins do not fold correctly and are subject to proteasomal degradation, resulting in PARPi sensitivity. In this study, we show that cell lines and patient-derived tumors, with highly disruptive BRCT domain mutations, have readily detectable BRCA1 protein expression, and are able to proliferate in the presence of PARPi. Peptide analyses reveal that chemo-resistant cancers contain residues encoded by BRCA1 intron 15. Mechanistically, cancers with BRCT domain mutations harbor BRCA1 gene breakpoints within or adjacent to Alu elements in intron 15; producing partial gene duplications, inversions and translocations, and terminating transcription prior to the mutation-containing BRCT domain. BRCA1 BRCT domain-deficient protein isoforms avoid mutation-induced proteasomal degradation, support homology-dependent DNA repair, and promote PARPi resistance. Taken together, Alu-mediated BRCA1 gene rearrangements are responsible for generating hypomorphic proteins, and may represent a biomarker of PARPi resistance.
The autophagy receptor p62/SQST-1 promotes proteostasis and longevity in C. elegans by inducing autophagy
Authors: Kumsta Caroline , Chang Jessica T. , Lee Reina , Tan Ee Phie , Yang Yongzhi , Loureiro Rute , Choy Elizabeth H. , Lim Shaun H. Y. , Saez Isabel , Springhorn Alexander , Hoppe Thorsten , Vilchez David , Hansen Malene 
Published: December 2019

AbstractAutophagy can degrade cargos with the help of selective autophagy receptors such as p62/SQSTM1, which facilitates the degradation of ubiquitinated cargo. While the process of autophagy has been linked to aging, the impact of selective autophagy in lifespan regulation remains unclear. We have recently shown in Caenorhabditis elegans that transcript levels of sqst-1/p62 increase upon a hormetic heat shock, suggesting a role of SQST-1/p62 in stress response and aging. Here, we find that sqst-1/p62 is required for hormetic benefits of heat shock, including longevity, improved neuronal proteostasis, and autophagy induction. Furthermore, overexpression of SQST-1/p62 is sufficient to induce autophagy in distinct tissues, extend lifespan, and improve the fitness of mutants with defects in proteostasis in an autophagy-dependent manner. Collectively, these findings illustrate that increased expression of a selective autophagy receptor is sufficient to induce autophagy, enhance proteostasis and extend longevity, and demonstrate an important role for sqst-1/p62 in proteotoxic stress responses.
Ensemble representations reveal distinct neural coding of visual working memory
Authors: Oh Byung-Il , Kim Yee-Joon , Kang Min-Suk 
Published: December 2019

AbstractWe characterized the population-level neural coding of ensemble representations in visual working memory from human electroencephalography. Ensemble representations provide a unique opportunity to investigate structured representations of working memory because the visual system encodes high-order summary statistics as well as noisy sensory inputs in a hierarchical manner. Here, we consistently observe stable coding of simple features as well as the ensemble mean in frontocentral electrodes, which even correlated with behavioral indices of the ensemble across individuals. In occipitoparietal electrodes, however, we find that remembered features are dynamically coded over time, whereas neural coding of the ensemble mean is absent in the old/new judgment task. In contrast, both dynamic and stable coding are found in the continuous estimation task. Our findings suggest that the prefrontal cortex holds behaviorally relevant abstract representations while visual representations in posterior and visual areas are modulated by the task demands.
Extracellular matrix hydrogel derived from decellularized tissues enables endodermal organoid culture
Authors: Giobbe Giovanni Giuseppe , Crowley Claire , Luni Camilla , Campinoti Sara , Khedr Moustafa , Kretzschmar Kai , De Santis Martina Maria , Zambaiti Elisa , Michielin Federica , Meran Laween , Hu Qianjiang , van Son Gijs , Urbani Luca , Manfredi Anna , Giomo Monica , Eaton Simon , Cacchiarelli Davide , Li Vivian S. W. , Clevers Hans , Bonfanti Paola , Elvassore Nicola , De Coppi Paolo 
Published: December 2019

AbstractOrganoids have extensive therapeutic potential and are increasingly opening up new avenues within regenerative medicine. However, their clinical application is greatly limited by the lack of effective GMP-compliant systems for organoid expansion in culture. Here, we envisage that the use of extracellular matrix (ECM) hydrogels derived from decellularized tissues (DT) can provide an environment capable of directing cell growth. These gels possess the biochemical signature of tissue-specific ECM and have the potential for clinical translation. Gels from decellularized porcine small intestine (SI) mucosa/submucosa enable formation and growth of endoderm-derived human organoids, such as gastric, hepatic, pancreatic, and SI. ECM gels can be used as a tool for direct human organoid derivation, for cell growth with a stable transcriptomic signature, and for in vivo organoid delivery. The development of these ECM-derived hydrogels opens up the potential for human organoids to be used clinically.
Acyl radical to rhodacycle addition and cyclization relay to access butterfly flavylium fluorophores
Authors: Yin Jiangliang , Zhang Yuming , Li Jian , Zhu Lei , Lan Yu , You Jingsong 
Published: December 2019

AbstractTransition metal-catalyzed C–H activation and radical reactions are two versatile strategies to construct diverse organic skeletons. Here we show the construction of a class of flavylium fluorophores via the merge of radical chemistry and C–H activation starting from (hetero)aryl ketones and alkynes. This protocol is not only applicable to aryl ketones but also to heteroaryl ketones such as thiophene, benzothiophene and benzofuran, thus leading to structural diversity. Mechanism studies, including control experiments, intermediate separation, radical trapping, EPR and ESI-HRMS experiments, demonstrate that the key step lies in the addition of the acyl radical generated by the copper-catalyzed C–C bond cleavage of aryl ketone to the rhodacycle formed via the C–H activation of aryl ketone. The flavylium fluorophores feature butterfly symmetrical configuration, nearly planar skeleton and delocalized positive charge, and exhibit intriguing photophysical properties, such as tunable absorption and emission wavelengths and high quantum yields.
Trained immunity modulates inflammation-induced fibrosis
Authors: Jeljeli Mohamed , Riccio Luiza Gama Coelho , Doridot Ludivine , Chêne Charlotte , Nicco Carole , Chouzenoux Sandrine , Deletang Quentin , Allanore Yannick , Kavian Niloufar , Batteux Frédéric 
Published: December 2019

AbstractChronic inflammation and fibrosis can result from inappropriately activated immune responses that are mediated by macrophages. Macrophages can acquire memory-like characteristics in response to antigen exposure. Here, we show the effect of BCG or low-dose LPS stimulation on macrophage phenotype, cytokine production, chromatin and metabolic modifications. Low-dose LPS training alleviates fibrosis and inflammation in a mouse model of systemic sclerosis (SSc), whereas BCG-training exacerbates disease in this model. Adoptive transfer of low-dose LPS-trained or BCG-trained macrophages also has beneficial or harmful effects, respectively. Furthermore, coculture with low-dose LPS trained macrophages reduces the fibro-inflammatory profile of fibroblasts from mice and patients with SSc, indicating that trained immunity might be a phenomenon that can be targeted to treat SSc and other autoimmune and inflammatory fibrotic disorders.
Report from a multidisciplinary meeting on anxiety as a non-motor manifestation of Parkinson’s disease
Authors: Pontone Gregory M. , Dissanayaka Nadeeka , Apostolova Liana , Brown Richard G. , Dobkin Roseanne , Dujardin Kathy , Friedman Joseph H. , Leentjens Albert F. G. , Lenze Eric J. , Marsh Laura , Mari Lynda , Monchi Oury , Richard Irene H. , Schrag Anette , Strafella Antonio P. , Vernaleo Beth , Weintraub Daniel , Mari Zoltan 
Published: December 2019

AbstractAnxiety is a severe problem for at least one-third of people living with Parkinson’s disease (PD). Anxiety appears to have a greater adverse impact on quality of life than motor impairment. Despite its high prevalence and impact on daily life, anxiety is often undiagnosed and untreated. To better address anxiety in PD, future research must improve knowledge about the mechanism of anxiety in PD and address the lack of empirical evidence from clinical trials. In response to these challenges, the Parkinson’s Foundation sponsored an expert meeting on anxiety on June 13th and 14th 2018. This paper summarizes the findings from that meeting informed by a review of the existing literature and discussions among patients, caregivers, and an international, clinician-scientist, expert panel working group. The goal is to provide recommendations to improve our understanding and treatment of anxiety in PD.
Activity of M3814, an Oral DNA-PK Inhibitor, In Combination with Topoisomerase II Inhibitors in Ovarian Cancer Models
Authors: Wise Hannah C. , Iyer Gopakumar V. , Moore Kathleen , Temkin Sarah M. , Gordon Sarah , Aghajanian Carol , Grisham Rachel N. 
Published: December 2019

AbstractDNA-dependent protein kinase (DNA-PK) has been shown to play a crucial role in repair of DNA double-strand breaks, facilitating nonhomologous end-joining. DNA-PK inhibitors have the potential to block DNA repair and therefore enhance DNA-damaging agents. M3814 is a DNA-PK inhibitor that has shown preclinical activity in combination with DNA-damaging agents, including radiotherapy and topoisomerase II inhibitors. Here we evaluated the activity of M3814 in combination with multiple topoisomerase II inhibitors, doxorubicin, etoposide, and pegylated liposomal doxorubicin (PLD) in vivo, utilizing ovarian cancer xenografts. Using cell lines representative of P53 wild-type ovarian cancer (A2780), and P53 mutant ovarian cancer (SKOV3), cells were implanted in the flank of athymic nude female mice. Mice were treated with vehicle, M3814 alone, topoisomerase II inhibitor alone, and M3814 in combination with topoisomerase II inhibitor, and change in tumor volume over time was documented. The addition of M3814 was well tolerated. We demonstrated that M3814 shows limited efficacy as a single agent in ovarian cancer models. The combination of M3814 with PLD showed enhanced activity over PLD as a single agent. Further study of this combination is warranted.