bluuebunny/crossref_metadata_2025_split huggingface dataset:
PLAU directs conversion of fibroblasts to inflammatory cancer-associated fibroblasts, promoting esophageal squamous cell carcinoma progression via uPAR/Akt/NF-κB/IL8 pathway
Authors: Fang Lingling , Che Yun , Zhang Chaoqi , Huang Jianbing , Lei Yuanyuan , Lu Zhiliang , Sun Nan , He Jie 
Published: February 2021

AbstractCancer-associated fibroblasts (CAFs) plays an important role in the tumor microenvironment. The heterogeneity of CAFs affects the effect of CAFs on promoting or inhibiting tumors, which can be regulated by other cells in the tumor microenvironment through paracrine methods. The urokinase-type plasminogen activator (PLAU) system mediates cell proliferation, migration, adhesion, and other functions through the proteolytic system, intracellular signal transduction, and chemokine activation. PLAU promotes tumor progression in many tumors. We explored the function of PLAU in ESCC and the influence of PLAU secreted by tumor cells on the heterogeneity of CAFs. We found that PLAU is highly expressed in ESCC, which is related to poor prognosis and can be used as a prognostic marker for ESCC. Through loss-of function and gain-of function experiments, we found that PLAU promoted ESCC proliferation and clone formation via MAPK pathway, and promotes migration by upregulating Slug and MMP9, which can be reversed by the MEK 1/2 inhibitor U0126. At the same time, through sequencing, cytokine detection, and RT-qPCR verification, we found that tumor cells secreted PLAU promoted the conversion of fibroblasts to inflammatory CAFs, which upregulated expression and secretion of IL8 via the uPAR/Akt/NF-κB pathway. The IL8 secreted by CAFs in turn promotes the high expression of PLAU in tumor cells and further promoted the progression of ESCC. In summary, PLAU was not only a prognostic marker of ESCC, which promoted tumor cell proliferation and migration, but also promoted the formation of inflammatory CAFs by the PLAU secreted by tumor cells.
Cas9-directed immune tolerance in humans—a model to evaluate regulatory T cells in gene therapy?
Authors: Wagner Dimitrios Laurin , Peter Lena , Schmueck-Henneresse Michael 
Published: February 2021

AbstractThe dichotomic nature of the adaptive immune response governs the outcome of clinical gene therapy. On the one hand, neutralizing antibodies and cytotoxic T cells can have a dramatic impact on the efficacy and safety of human gene therapies. On the other hand, regulatory T cells (Treg) can promote tolerance toward transgenes thereby enabling long-term benefits of in vivo gene therapy after a single administration. Pre-existing antibodies and T cell immunity has been a major obstacle for in vivo gene therapies with viral vectors. As CRISPR-Cas9 gene editing advances toward the clinics, the technology’s inherent immunogenicity must be addressed in order to guide clinical treatment decisions. This review summarizes the recent evidence on Cas9-specific immunity in humans—including early results from clinical trials—and discusses the risks for in vivo gene therapies. Finally, we focus on solutions and highlight the potential role of Cas9-specific Treg cells to promote immune tolerance. As a “beneficial alliance” beyond Cas9-immunity, antigen-specific Treg cells may serve as a living and targeted immunosuppressant to increase safety and efficacy of gene therapy.
Genome sequence and evolution ofBetula platyphylla
Authors: Chen Su , Wang Yucheng , Yu Lili , Zheng Tao , Wang Sui , Yue Zhen , Jiang Jing , Kumari Sapna , Zheng Chunfang , Tang Haibao , Li Jun , Li Yuqi , Chen Jiongjiong , Zhang Wenbo , Kuang Hanhui , Robertson Jon S , Zhao Patrick X , Li Huiyu , Shu Shengqiang , Yordanov Yordan S , Huang Haijiao , Goodstein David M , Gai Ying , Qi Qi , Min JiuMeng , Xu ChunYan , Wang SongBo , Qu Guan-Zheng , Paterson Andrew H , Sankoff David , Wei Hairong , Liu Guifeng , Yang Chuanping 
Published: February 2021

AbstractBetula L. (birch) is a pioneer hardwood tree species with ecological, economic, and evolutionary importance in the Northern Hemisphere. We sequenced the Betula platyphylla genome and assembled the sequences into 14 chromosomes. The Betula genome lacks evidence of recent whole-genome duplication and has the same paleoploidy level as Vitis vinifera and Prunus mume. Phylogenetic analysis of lignin pathway genes coupled with tissue-specific expression patterns provided clues for understanding the formation of higher ratios of syringyl to guaiacyl lignin observed in Betula species. Our transcriptome analysis of leaf tissues under a time-series cold stress experiment revealed the presence of the MEKK1–MKK2–MPK4 cascade and six additional mitogen-activated protein kinases that can be linked to a gene regulatory network involving many transcription factors and cold tolerance genes. Our genomic and transcriptome analyses provide insight into the structures, features, and evolution of the B. platyphylla genome. The chromosome-level genome and gene resources of B. platyphylla obtained in this study will facilitate the identification of important and essential genes governing important traits of trees and genetic improvement of B. platyphylla.
Rare genetic variants affecting urine metabolite levels link population variation to inborn errors of metabolism
Authors: Cheng Yurong , Schlosser Pascal , Hertel Johannes , Sekula Peggy , Oefner Peter J. , Spiekerkoetter Ute , Mielke Johanna , Freitag Daniel F. , Schmidts Miriam ,   GCKD Investigators, Oefner Peter J. , Kronenberg Florian , Eckardt Kai-Uwe , Kronenberg Florian , Eckardt Kai-Uwe , Thiele Ines , Li Yong , Köttgen Anna 
Published: February 2021

AbstractMetabolite levels in urine may provide insights into genetic mechanisms shaping their related pathways. We therefore investigate the cumulative contribution of rare, exonic genetic variants on urine levels of 1487 metabolites and 53,714 metabolite ratios among 4864 GCKD study participants. Here we report the detection of 128 significant associations involving 30 unique genes, 16 of which are known to underlie inborn errors of metabolism. The 30 genes are strongly enriched for shared expression in liver and kidney (odds ratio = 65, p-FDR = 3e−7), with hepatocytes and proximal tubule cells as driving cell types. Use of UK Biobank whole-exome sequencing data links genes to diseases connected to the identified metabolites. In silico constraint-based modeling of gene knockouts in a virtual whole-body, organ-resolved metabolic human correctly predicts the observed direction of metabolite changes, highlighting the potential of linking population genetics to modeling. Our study implicates candidate variants and genes for inborn errors of metabolism.
Exciton–phonon coupling strength in single-layer MoSe2 at room temperature
Authors: Li Donghai , Trovatello Chiara , Dal Conte Stefano , Nuß Matthias , Soavi Giancarlo , Wang Gang , Ferrari Andrea C. , Cerullo Giulio , Brixner Tobias 
Published: February 2021

AbstractSingle-layer transition metal dichalcogenides are at the center of an ever increasing research effort both in terms of fundamental physics and applications. Exciton–phonon coupling plays a key role in determining the (opto)electronic properties of these materials. However, the exciton–phonon coupling strength has not been measured at room temperature. Here, we use two-dimensional micro-spectroscopy to determine exciton–phonon coupling of single-layer MoSe2. We detect beating signals as a function of waiting time induced by the coupling between A excitons and A′1 optical phonons. Analysis of beating maps combined with simulations provides the exciton–phonon coupling. We get a Huang–Rhys factor ~1, larger than in most other inorganic semiconductor nanostructures. Our technique offers a unique tool to measure exciton–phonon coupling also in other heterogeneous semiconducting systems, with a spatial resolution ~260 nm, and provides design-relevant parameters for the development of optoelectronic devices.
GWAS for autoimmune Addison’s disease identifies multiple risk loci and highlights AIRE in disease susceptibility
Authors: Eriksson Daniel , Røyrvik Ellen Christine , Aranda-Guillén Maribel , Berger Amund Holte , Landegren Nils , Artaza Haydee , Hallgren Åsa , Grytaas Marianne Aardal , Ström Sara , Bratland Eirik , Botusan Ileana Ruxandra , Oftedal Bergithe Eikeland , Breivik Lars , Vaudel Marc , Helgeland Øyvind , Falorni Alberto , Jørgensen Anders Palmstrøm , Hulting Anna-Lena , Svartberg Johan , Ekwall Olov , Fougner Kristian Johan , Wahlberg Jeanette , Nedrebø Bjørn Gunnar , Dahlqvist Per ,   The Norwegian Addison Registry Study Group, Ræder Helge , Jovanovic Nevena , Reisegg Sigfrid Christine , Hølleland Geir , Carlsen Siri , Berg Tore Julsrud , Eggesbø Jan Bertil , Svendsen Thomas , Lima Kari , Nermoen Ingrid , Whitfield Rolf , Sollid Stina , Aarskog Dagfinn , Korsgaard Elin , Sæta Solveig , Finnes Trine , Valland Susanna Fonneland , Fossum Christian , Brevik Eli , Moe Ragnar Bekkhus , Svendsen Margrethe , Debowska Aleksandra , Milova Petya , Holte Synnøve , Tomkowicz Aneta Eva , Sørmo Dag Eirik , Svare Anders , Rensvik Marthe Landsverk , Revheim Randi , Haug Thor , Blix Ivar , Jensen Lars Petter ,   The Swedish Addison Registry Study Group, Åkerman Anna-Karin , Hulting Anna-Lena , Lindberg Bengt , Kriström Berit , Waldenström Erik , Johannsson Gudmundur , Skov Jakob , Wahlberg Jeanette , Duchen Karel , Isaksson Magnus , Elfving Maria , Stenlid Maria Halldin , Nilsson Ola , Kämpe Olle , Ekwall Olov , Dahlqvist Per , Bergthorsdottir Ragnhildur , Nergårdh Ricard , Björnsdottir Sigridur , Bensing Sophie , Olsson Tommy , Knappskog Per Morten , Wolff Anette Susanne Bøe , Bensing Sophie , Johansson Stefan , Kämpe Olle , Husebye Eystein Sverre 
Published: February 2021

AbstractAutoimmune Addison’s disease (AAD) is characterized by the autoimmune destruction of the adrenal cortex. Low prevalence and complex inheritance have long hindered successful genetic studies. We here report the first genome-wide association study on AAD, which identifies nine independent risk loci (P < 5 × 10−8). In addition to loci implicated in lymphocyte function and development shared with other autoimmune diseases such as HLA, BACH2, PTPN22 and CTLA4, we associate two protein-coding alterations in Autoimmune Regulator (AIRE) with AAD. The strongest, p.R471C (rs74203920, OR = 3.4 (2.7–4.3), P = 9.0 × 10−25) introduces an additional cysteine residue in the zinc-finger motif of the second PHD domain of the AIRE protein. This unbiased elucidation of the genetic contribution to development of AAD points to the importance of central immunological tolerance, and explains 35–41% of heritability (h2).
Multi-level quantum noise spectroscopy
Authors: Sung Youngkyu , Vepsäläinen Antti , Braumüller Jochen , Yan Fei , Wang Joel I-Jan , Kjaergaard Morten , Winik Roni , Krantz Philip , Bengtsson Andreas , Melville Alexander J. , Niedzielski Bethany M. , Schwartz Mollie E. , Kim David K. , Yoder Jonilyn L. , Orlando Terry P. , Gustavsson Simon , Oliver William D. 
Published: February 2021

AbstractSystem noise identification is crucial to the engineering of robust quantum systems. Although existing quantum noise spectroscopy (QNS) protocols measure an aggregate amount of noise affecting a quantum system, they generally cannot distinguish between the underlying processes that contribute to it. Here, we propose and experimentally validate a spin-locking-based QNS protocol that exploits the multi-level energy structure of a superconducting qubit to achieve two notable advances. First, our protocol extends the spectral range of weakly anharmonic qubit spectrometers beyond the present limitations set by their lack of strong anharmonicity. Second, the additional information gained from probing the higher-excited levels enables us to identify and distinguish contributions from different underlying noise mechanisms.
Regulatory inter-domain interactions influence Hsp70 recruitment to the DnaJB8 chaperone
Authors: Ryder Bryan D. , Matlahov Irina , Bali Sofia , Vaquer-Alicea Jaime , van der Wel Patrick C. A. , Joachimiak Lukasz A. 
Published: February 2021

AbstractThe Hsp40/Hsp70 chaperone families combine versatile folding capacity with high substrate specificity, which is mainly facilitated by Hsp40s. The structure and function of many Hsp40s remain poorly understood, particularly oligomeric Hsp40s that suppress protein aggregation. Here, we used a combination of biochemical and structural approaches to shed light on the domain interactions of the Hsp40 DnaJB8, and how they may influence recruitment of partner Hsp70s. We identify an interaction between the J-Domain (JD) and C-terminal domain (CTD) of DnaJB8 that sequesters the JD surface, preventing Hsp70 interaction. We propose a model for DnaJB8-Hsp70 recruitment, whereby the JD-CTD interaction of DnaJB8 acts as a reversible switch that can control the binding of Hsp70. These findings suggest that the evolutionarily conserved CTD of DnaJB8 is a regulatory element of chaperone activity in the proteostasis network.
Probing electronic structure in berkelium and californium via an electron microscopy nanosampling approach
Authors: Müller Alexander , Deblonde Gauthier J.-P. , Ercius Peter , Zeltmann Steven E. , Abergel Rebecca J. , Minor Andrew M. 
Published: February 2021

AbstractDue to their rarity and radioactive nature, comparatively little is known about the actinides, particularly those with atomic numbers higher than that of plutonium, and their compounds. In this work, we describe how transmission electron microscopy can provide comprehensive, safe, and cost-effective characterization using only single nanogram amounts of highly-radioactive, solid compounds. Chlorides of the rare elements berkelium and californium are dropcast and then converted in situ to oxides using the electron beam. The f-band occupancies are probed using electron energy loss spectroscopy and an unexpectedly weak spin-orbit-coupling is identified for berkelium. In contrast, californium follows a jj coupling scheme. These results have important implications for the chemistries of these elements and solidify the status of californium as a transitional element in the actinide series.
RNA secondary structure prediction using deep learning with thermodynamic integration
Authors: Sato Kengo , Akiyama Manato , Sakakibara Yasubumi 
Published: February 2021

AbstractAccurate predictions of RNA secondary structures can help uncover the roles of functional non-coding RNAs. Although machine learning-based models have achieved high performance in terms of prediction accuracy, overfitting is a common risk for such highly parameterized models. Here we show that overfitting can be minimized when RNA folding scores learnt using a deep neural network are integrated together with Turner’s nearest-neighbor free energy parameters. Training the model with thermodynamic regularization ensures that folding scores and the calculated free energy are as close as possible. In computational experiments designed for newly discovered non-coding RNAs, our algorithm (MXfold2) achieves the most robust and accurate predictions of RNA secondary structures without sacrificing computational efficiency compared to several other algorithms. The results suggest that integrating thermodynamic information could help improve the robustness of deep learning-based predictions of RNA secondary structure.
A genome-wide CRISPR screen identifies host factors that regulate SARS-CoV-2 entry
Authors: Zhu Yunkai , Feng Fei , Hu Gaowei , Wang Yuyan , Yu Yin , Zhu Yuanfei , Xu Wei , Cai Xia , Sun Zhiping , Han Wendong , Ye Rong , Qu Di , Ding Qiang , Huang Xinxin , Chen Hongjun , Xu Wei , Xie Youhua , Cai Qiliang , Yuan Zhenghong , Zhang Rong 
Published: February 2021

AbstractThe global spread of SARS-CoV-2 is posing major public health challenges. One feature of SARS-CoV-2 spike protein is the insertion of multi-basic residues at the S1/S2 subunit cleavage site. Here, we find that the virus with intact spike (Sfull) preferentially enters cells via fusion at the plasma membrane, whereas a clone (Sdel) with deletion disrupting the multi-basic S1/S2 site utilizes an endosomal entry pathway. Using Sdel as model, we perform a genome-wide CRISPR screen and identify several endosomal entry-specific regulators. Experimental validation of hits from the CRISPR screen shows that host factors regulating the surface expression of angiotensin-converting enzyme 2 (ACE2) affect entry of Sfull virus. Animal-to-animal transmission with the Sdel virus is reduced compared to Sfull in the hamster model. These findings highlight the critical role of the S1/S2 boundary of SARS-CoV-2 spike protein in modulating virus entry and transmission and provide insights into entry of coronaviruses.
Structural mechanism of bivalent histone H3K4me3K9me3 recognition by the Spindlin1/C11orf84 complex in rRNA transcription activation
Authors: Du Yongming , Yan Yinxia , Xie Si , Huang Hao , Wang Xin , Ng Ray Kit , Zhou Ming-Ming , Qian Chengmin 
Published: February 2021

AbstractSpindlin1 is a unique multivalent epigenetic reader that facilitates ribosomal RNA transcription. In this study, we provide molecular and structural basis by which Spindlin1 acts in complex with C11orf84 to preferentially recognize non-canonical bivalent mark of trimethylated lysine 4 and lysine 9 present on the same histone H3 tail (H3K4me3K9me3). We demonstrate that C11orf84 binding stabilizes Spindlin1 and enhances its association with bivalent H3K4me3K9me3 mark. The functional analysis suggests that Spindlin1/C11orf84 complex can displace HP1 proteins from H3K4me3K9me3-enriched rDNA loci, thereby facilitating the conversion of these poised rDNA repeats from the repressed state to the active conformation, and the consequent recruitment of RNA Polymerase I for rRNA transcription. Our study uncovers a previously unappreciated mechanism of bivalent H3K4me3K9me3 recognition by Spindlin1/C11orf84 complex required for activation of rRNA transcription.
Addressable nanoantennas with cleared hotspots for single-molecule detection on a portable smartphone microscope
Authors: Trofymchuk Kateryna , Glembockyte Viktorija , Grabenhorst Lennart , Steiner Florian , Vietz Carolin , Close Cindy , Pfeiffer Martina , Richter Lars , Schütte Max L. , Selbach Florian , Yaadav Renukka , Zähringer Jonas , Wei Qingshan , Ozcan Aydogan , Lalkens Birka , Acuna Guillermo P. , Tinnefeld Philip 
Published: February 2021

AbstractThe advent of highly sensitive photodetectors and the development of photostabilization strategies made detecting the fluorescence of single molecules a routine task in many labs around the world. However, to this day, this process requires cost-intensive optical instruments due to the truly nanoscopic signal of a single emitter. Simplifying single-molecule detection would enable many exciting applications, e.g., in point-of-care diagnostic settings, where costly equipment would be prohibitive. Here, we introduce addressable NanoAntennas with Cleared HOtSpots (NACHOS) that are scaffolded by DNA origami nanostructures and can be specifically tailored for the incorporation of bioassays. Single emitters placed in NACHOS emit up to 461-fold (average of 89 ± 7-fold) brighter enabling their detection with a customary smartphone camera and an 8-US-dollar objective lens. To prove the applicability of our system, we built a portable, battery-powered smartphone microscope and successfully carried out an exemplary single-molecule detection assay for DNA specific to antibiotic-resistant Klebsiella pneumonia on the road.
Post-exposure protection of SARS-CoV-2 lethal infected K18-hACE2 transgenic mice by neutralizing human monoclonal antibody
Authors: Rosenfeld Ronit , Noy-Porat Tal , Mechaly Adva , Makdasi Efi , Levy Yinon , Alcalay Ron , Falach Reut , Aftalion Moshe , Epstein Eyal , Gur David , Chitlaru Theodor , Vitner Einat B. , Melamed Sharon , Politi Boaz , Zauberman Ayelet , Lazar Shirley , Beth-Din Adi , Evgy Yentl , Yitzhaki Shmuel , Shapira Shmuel C. , Israely Tomer , Mazor Ohad 
Published: February 2021

AbstractThe coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), exhibits high levels of mortality and morbidity and has dramatic consequences on human life, sociality and global economy. Neutralizing antibodies constitute a highly promising approach for treating and preventing infection by this novel pathogen. In the present study, we characterize and further evaluate the recently identified human monoclonal MD65 antibody for its ability to provide protection against a lethal SARS-CoV-2 infection of K18-hACE2 transgenic mice. Eighty percent of the untreated mice succumbed 6–9 days post-infection, while administration of the MD65 antibody as late as 3 days after exposure rescued all infected animals. In addition, the efficiency of the treatment is supported by prevention of morbidity and ablation of the load of infective virions in the lungs of treated animals. The data demonstrate the therapeutic value of human monoclonal antibodies as a life-saving treatment for severe COVID-19 infection.
Targeting IL-21 to tumor-reactive T cells enhances memory T cell responses and anti-PD-1 antibody therapy
Authors: Li Ying , Cong Yanni , Jia Mingming , He Qianqian , Zhong Haiqing , Zhao Yun , Li Hang , Yan Meining , You Jia , Liu Jia , Chen Lieping , Hang Haiying , Wang Shengdian 
Published: February 2021

AbstractT cell rejuvenation by PD-1/PD-L1 blockade, despite emerging as a highly promising therapy for advanced cancers, is only beneficial for a minority of treated patients. There is evidence that a lack of efficient T cell activation may be responsible for the failure. Here, we demonstrate that IL-21 can be targeted to tumor-reactive T cells by fusion of IL-21 to anti-PD-1 antibody. To our surprise, the fusion protein PD-1Ab21 promotes the generation of memory stem T cells (TSCM) with enhanced cell proliferation. PD-1Ab21 treatment show potent antitumor effects in established tumor-bearing mice accompanied with an increased frequency of TSCM and robust expansion of tumor-specific CD8+ T cells with a memory phenotype, and is superior to a combination of PD-1 blockade and IL-21 infusion. Therefore, we have developed a potential strategy to improve the therapeutic effects of immune checkpoint blockade by simultaneously targeting cytokines to tumor-reactive T cells.
Diagnostic accuracy of cytology for the detection of endometrial cancer in urine and vaginal samples
Authors: O’Flynn Helena , Ryan Neil A. J. , Narine Nadira , Shelton David , Rana Durgesh , Crosbie Emma J. 
Published: February 2021

AbstractPostmenopausal bleeding triggers urgent investigation by sequential invasive tests that are avoidable for the 90–95% of women who do not have endometrial cancer. A simple, non-invasive tool that accurately identifies cancer and safely reassures healthy women could transform patient care. Here we report, in a cross-sectional diagnostic accuracy study of 103 women with known cancer and 113 with unexplained postmenopausal bleeding, that urine and vaginal cytology has a combined sensitivity of 91.7% (95% CI 85.0%, 96.1%) and specificity of 88.8% (81.2%, 94.1%) for gynecological cancer detection. Cytology identifies 91 endometrial, two fallopian tube and one cervical cancer from 103 known cancer cases. In women with unexplained postmenopausal bleeding, cytology identifies all four endometrial cancers and three others (cervical, ovarian and bladder), for a 12/107 (11.2%) false positive rate. We show proof-of-principle that endometrial cancer can be detected in urine and vaginal fluid. Prospective validation of these findings will support incorporation of this non-invasive test into clinical practice.