bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypothermic oxygenated perfusion inhibits HECTD3-mediated TRAF3 polyubiquitination to alleviate DCD liver ischemia-reperfusion injury
Authors: Zhou Wei , Zhong Zibiao , Lin Danni , Liu Zhongzhong , Zhang Qiuyan , Xia Haoyang , Peng Sheng , Liu Anxiong , Lu Zhongshan , Wang Yanfeng , Ye Shaojun , Ye Qifa 
Published: February 2021

AbstractIschemia-reperfusion injury (IRI) is an inevitable and serious clinical problem in donations after heart death (DCD) liver transplantation. Excessive sterile inflammation plays a fateful role in liver IRI. Hypothermic oxygenated perfusion (HOPE), as an emerging organ preservation technology, has a better preservation effect than cold storage (CS) for reducing liver IRI, in which regulating inflammation is one of the main mechanisms. HECTD3, a new E3 ubiquitin ligase, and TRAF3 have an essential role in inflammation. However, little is known about HECTD3 and TRAF3 in HOPE-regulated liver IRI. Here, we aimed to investigate the effects of HOPE on liver IRI in a DCD rat model and explore the roles of HECTD3 and TRAF3 in its pathogenesis. We found that HOPE significantly improved liver damage, including hepatocyte and liver sinusoidal endothelial cell injury, and reduced DCD liver inflammation. Mechanistically, both the DOC and HECT domains of HECTD3 directly interacted with TRAF3, and the catalytic Cys (C832) in the HECT domain promoted the K63-linked polyubiquitination of TRAF3 at Lys138. Further, the ubiquitinated TRAF3 at Lys138 increased oxidative stress and activated the NF-κB inflammation pathway to induce liver IRI in BRL-3A cells under hypoxia/reoxygenation conditions. Finally, we confirmed that the expression of HECTD3 and TRAF3 was obviously increased in human DCD liver transplantation specimens. Overall, these findings demonstrated that HOPE can protect against DCD liver transplantation-induced-liver IRI by reducing inflammation via HECTD3-mediated TRAF3 K63-linked polyubiquitination. Therefore, HOPE regulating the HECTD3/TRAF3 pathway is a novel target for improving IRI in DCD liver transplantation.
Mutant p53 promotes RCP-dependent chemoresistance coinciding with increased delivery of P-glycoprotein to the plasma membrane
Authors: Phatak Vinaya , von Grabowiecki Yannick , Janus Justyna , Officer Leah , Behan Caron , Aschauer Lydia , Pinon Lucia , Mackay Hannah , Zanivan Sara , Norman Jim C. , Kelly Michael , Le Quesne John , Muller Patricia A. J. 
Published: February 2021

AbstractTP53 is the most frequently mutated gene in cancers. Mutations lead to loss of p53 expression or expression of a mutant protein. Mutant p53 proteins commonly lose wild-type function, but can also acquire novel functions in promoting metastasis and chemoresistance. Previously, we uncovered a role for Rab-coupling protein (RCP) in mutant p53-dependent invasion. RCP promotes endosomal recycling and signalling of integrins and receptor tyrosine kinases. In a screen to identify novel RCP-interacting proteins, we discovered P-glycoprotein (P-gp). Thus, we hypothesised that mutant p53 could promote chemoresistance through RCP-dependent recycling of P-gp. The interaction between RCP and P-gp was verified endogenously and loss of RCP or mutant p53 rendered cells more sensitive to cisplatin and etoposide. In mutant p53 cells we detected an RCP-dependent delivery of P-gp to the plasma membrane upon drug treatment and decreased retention of P-gp substrates. A co-localisation of P-gp and RCP was seen in mutant p53 cells, but not in p53-null cells upon chemotherapeutic exposure. In conclusion, mutant p53 expression enhanced co-localisation of P-gp and RCP to allow for rapid delivery of P-gp to the plasma membrane and increased resistance to chemotherapeutics.
Establishment of a novel mesenchymal stem cell-based regimen for chronic myeloid leukemia differentiation therapy
Authors: Zuo Shiman , Sun Luchen , Wang Yuxin , Chen Bing , Wang Jingyue , Ge Xiangyu , Lu Yan , Yang Nanfei , Shen Pingping 
Published: February 2021

AbstractChronic myeloid leukemia (CML) is characterized by the accumulation of malignant and immature white blood cells which spread to the peripheral blood and other tissues/organs. Despite the fact that current tyrosine kinase inhibitors (TKIs) are capable of achieving the complete remission by reducing the tumor burden, severe adverse effects often occur in CML patients treated with TKIs. The differentiation therapy exhibits therapeutic potential to improve cure rates in leukemia, as evidenced by the striking success of all-trans-retinoic acid in acute promyelocytic leukemia treatment. However, there is still a lack of efficient differentiation therapy strategy in CML. Here we showed that MPL, which encodes the thrombopoietin receptor driving the development of hematopoietic stem/progenitor cells, decreased along with the progression of CML. We first elucidated that MPL signaling blockade impeded the megakaryocytic differentiation and contributed to the progression of CML. While allogeneic human umbilical cord-derived mesenchymal stem cells (UC-MSCs) treatment efficiently promoted megakaryocytic lineage differentiation of CML cells through restoring the MPL expression and activating MPL signaling. UC-MSCs in combination with eltrombopag, a non-peptide MPL agonist, further activated JAK/STAT and MAPK signaling pathways through MPL and exerted a synergetic effect on enhancing CML cell differentiation. The established combinational treatment not only markedly reduced the CML burden but also significantly eliminated CML cells in a xenograft CML model. We provided a new molecular insight of thrombopoietin (TPO) and MPL signaling in MSCs-mediated megakaryocytic differentiation of CML cells. Furthermore, a novel anti-CML treatment regimen that uses the combination of UC-MSCs and eltrombopag shows therapeutic potential to overcome the differentiation blockade in CML.
Short antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats
Authors: Derbis Magdalena , Kul Emre , Niewiadomska Daria , Sekrecki Michał , Piasecka Agnieszka , Taylor Katarzyna , Hukema Renate K. , Stork Oliver , Sobczak Krzysztof 
Published: February 2021

AbstractFragile X-associated tremor/ataxia syndrome (FXTAS) is an incurable neurodegenerative disorder caused by expansion of CGG repeats in theFMR15’UTR. The RNA containing expanded CGG repeats (rCGGexp) causes cell damage by interaction with complementary DNA, forming R-loop structures, sequestration of nuclear proteins involved in RNA metabolism and initiation of translation of polyglycine-containing protein (FMRpolyG), which forms nuclear insoluble inclusions. Here we show the therapeutic potential of short antisense oligonucleotide steric blockers (ASOs) targeting directly the rCGGexp. In nuclei of FXTAS cells ASOs affect R-loop formation and correct miRNA biogenesis and alternative splicing, indicating that nuclear proteins are released from toxic sequestration. In cytoplasm, ASOs significantly decrease the biosynthesis and accumulation of FMRpolyG. Delivery of ASO into a brain of FXTAS mouse model reduces formation of inclusions, improves motor behavior and corrects gene expression profile with marginal signs of toxicity after a few weeks from a treatment.
A simple low-latency real-time certifiable quantum random number generator
Authors: Zhang Yanbao , Lo Hsin-Pin , Mink Alan , Ikuta Takuya , Honjo Toshimori , Takesue Hiroki , Munro William J. 
Published: February 2021

AbstractQuantum random numbers distinguish themselves from others by their intrinsic unpredictability arising from the principles of quantum mechanics. As such they are extremely useful in many scientific and real-world applications with considerable efforts going into their realizations. Most demonstrations focus on high asymptotic generation rates. For this goal, a large number of repeated trials are required to accumulate a significant store of certifiable randomness, resulting in a high latency between the initial request and the delivery of the requested random bits. Here we demonstrate low-latency real-time certifiable randomness generation from measurements on photonic time-bin states. For this, we develop methods to certify randomness taking into account adversarial imperfections in both the state preparation and the measurement apparatus. Every 0.12 s we generate a block of 8192 random bits which are certifiable against all quantum adversaries with an error bounded by 2−64. Our quantum random number generator is thus well suited for realizing a continuously-operating, high-security and high-speed quantum randomness beacon.
Alternative lengthening of telomeres in childhood neuroblastoma from genome to proteome
Authors: Hartlieb Sabine A. , Sieverling Lina , Nadler-Holly Michal , Ziehm Matthias , Toprak Umut H. , Herrmann Carl , Ishaque Naveed , Okonechnikov Konstantin , Gartlgruber Moritz , Park Young-Gyu , Wecht Elisa Maria , Savelyeva Larissa , Henrich Kai-Oliver , Rosswog Carolina , Fischer Matthias , Hero Barbara , Jones David T. W. , Pfaff Elke , Witt Olaf , Pfister Stefan M. , Volckmann Richard , Koster Jan , Kiesel Katharina , Rippe Karsten , Taschner-Mandl Sabine , Ambros Peter , Brors Benedikt , Selbach Matthias , Feuerbach Lars , Westermann Frank 
Published: February 2021

AbstractTelomere maintenance by telomerase activation or alternative lengthening of telomeres (ALT) is a major determinant of poor outcome in neuroblastoma. Here, we screen for ALT in primary and relapsed neuroblastomas (n = 760) and characterize its features using multi-omics profiling. ALT-positive tumors are molecularly distinct from other neuroblastoma subtypes and enriched in a population-based clinical sequencing study cohort for relapsed cases. They display reduced ATRX/DAXX complex abundance, due to either ATRX mutations (55%) or low protein expression. The heterochromatic histone mark H3K9me3 recognized by ATRX is enriched at the telomeres of ALT-positive tumors. Notably, we find a high frequency of telomeric repeat loci with a neuroblastoma ALT-specific hotspot on chr1q42.2 and loss of the adjacent chromosomal segment forming a neo-telomere. ALT-positive neuroblastomas proliferate slowly, which is reflected by a protracted clinical course of disease. Nevertheless, children with an ALT-positive neuroblastoma have dismal outcome.
Comparison of rhesus and cynomolgus macaques as an infection model for COVID-19
Authors: Salguero Francisco J. , White Andrew D. , Slack Gillian S. , Fotheringham Susan A. , Bewley Kevin R. , Gooch Karen E. , Longet Stephanie , Humphries Holly E. , Watson Robert J. , Hunter Laura , Ryan Kathryn A. , Hall Yper , Sibley Laura , Sarfas Charlotte , Allen Lauren , Aram Marilyn , Brunt Emily , Brown Phillip , Buttigieg Karen R. , Cavell Breeze E. , Cobb Rebecca , Coombes Naomi S. , Darby Alistair , Daykin-Pont Owen , Elmore Michael J. , Garcia-Dorival Isabel , Gkolfinos Konstantinos , Godwin Kerry J. , Gouriet Jade , Halkerston Rachel , Harris Debbie J. , Hender Thomas , Ho Catherine M. K. , Kennard Chelsea L. , Knott Daniel , Leung Stephanie , Lucas Vanessa , Mabbutt Adam , Morrison Alexandra L. , Nelson Charlotte , Ngabo Didier , Paterson Jemma , Penn Elizabeth J. , Pullan Steve , Taylor Irene , Tipton Tom , Thomas Stephen , Tree Julia A. , Turner Carrie , Vamos Edith , Wand Nadina , Wiblin Nathan R. , Charlton Sue , Dong Xiaofeng , Hallis Bassam , Pearson Geoffrey , Rayner Emma L. , Nicholson Andrew G. , Funnell Simon G. , Hiscox Julian A. , Dennis Mike J. , Gleeson Fergus V. , Sharpe Sally , Carroll Miles W. 
Published: February 2021

AbstractA novel coronavirus, SARS-CoV-2, has been identified as the causative agent of the current COVID-19 pandemic. Animal models, and in particular non-human primates, are essential to understand the pathogenesis of emerging diseases and to assess the safety and efficacy of novel vaccines and therapeutics. Here, we show that SARS-CoV-2 replicates in the upper and lower respiratory tract and causes pulmonary lesions in both rhesus and cynomolgus macaques. Immune responses against SARS-CoV-2 are also similar in both species and equivalent to those reported in milder infections and convalescent human patients. This finding is reiterated by our transcriptional analysis of respiratory samples revealing the global response to infection. We describe a new method for lung histopathology scoring that will provide a metric to enable clearer decision making for this key endpoint. In contrast to prior publications, in which rhesus are accepted to be the preferred study species, we provide convincing evidence that both macaque species authentically represent mild to moderate forms of COVID-19 observed in the majority of the human population and both species should be used to evaluate the safety and efficacy of interventions against SARS-CoV-2. Importantly, accessing cynomolgus macaques will greatly alleviate the pressures on current rhesus stocks.
Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer
Authors: Mizuta Hayato , Okada Koutaroh , Araki Mitsugu , Adachi Jun , Takemoto Ai , Kutkowska Justyna , Maruyama Kohei , Yanagitani Noriko , Oh-hara Tomoko , Watanabe Kana , Tamai Keiichi , Friboulet Luc , Katayama Kazuhiro , Ma Biao , Sasakura Yoko , Sagae Yukari , Kukimoto-Niino Mutsuko , Shirouzu Mikako , Takagi Satoshi , Simizu Siro , Nishio Makoto , Okuno Yasushi , Fujita Naoya , Katayama Ryohei 
Published: February 2021

AbstractALK gene rearrangement was observed in 3%–5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI–resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.
Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia
Authors: Colombo Alessio , Dinkel Lina , Müller Stephan A. , Sebastian Monasor Laura , Schifferer Martina , Cantuti-Castelvetri Ludovico , König Jasmin , Vidatic Lea , Bremova-Ertl Tatiana , Lieberman Andrew P. , Hecimovic Silva , Simons Mikael , Lichtenthaler Stefan F. , Strupp Michael , Schneider Susanne A. , Tahirovic Sabina 
Published: February 2021

AbstractNiemann-Pick type C disease is a rare neurodegenerative disorder mainly caused by mutations in NPC1, resulting in abnormal late endosomal/lysosomal lipid storage. Although microgliosis is a prominent pathological feature, direct consequences of NPC1 loss on microglial function remain not fully characterized. We discovered pathological proteomic signatures and phenotypes in NPC1-deficient murine models and demonstrate a cell autonomous function of NPC1 in microglia. Loss of NPC1 triggers enhanced phagocytic uptake and impaired myelin turnover in microglia that precede neuronal death. Npc1−/− microglia feature a striking accumulation of multivesicular bodies and impaired trafficking of lipids to lysosomes while lysosomal degradation function remains preserved. Molecular and functional defects were also detected in blood-derived macrophages of NPC patients that provide a potential tool for monitoring disease. Our study underscores an essential cell autonomous role for NPC1 in immune cells and implies microglial therapeutic potential.
Ensembled deep learning model outperforms human experts in diagnosing biliary atresia from sonographic gallbladder images
Authors: Zhou Wenying , Yang Yang , Yu Cheng , Liu Juxian , Duan Xingxing , Weng Zongjie , Chen Dan , Liang Qianhong , Fang Qin , Zhou Jiaojiao , Ju Hao , Luo Zhenhua , Guo Weihao , Ma Xiaoyan , Xie Xiaoyan , Wang Ruixuan , Zhou Luyao 
Published: February 2021

AbstractIt is still challenging to make accurate diagnosis of biliary atresia (BA) with sonographic gallbladder images particularly in rural area without relevant expertise. To help diagnose BA based on sonographic gallbladder images, an ensembled deep learning model is developed. The model yields a patient-level sensitivity 93.1% and specificity 93.9% [with areas under the receiver operating characteristic curve of 0.956 (95% confidence interval: 0.928-0.977)] on the multi-center external validation dataset, superior to that of human experts. With the help of the model, the performances of human experts with various levels are improved. Moreover, the diagnosis based on smartphone photos of sonographic gallbladder images through a smartphone app and based on video sequences by the model still yields expert-level performances. The ensembled deep learning model in this study provides a solution to help radiologists improve the diagnosis of BA in various clinical application scenarios, particularly in rural and undeveloped regions with limited expertise.
Asymmetric water transport in dense leaf cuticles and cuticle-inspired compositionally graded membranes
Authors: Kamtsikakis Aristotelis , Baales Johanna , Zeisler-Diehl Viktoria V. , Vanhecke Dimitri , Zoppe Justin O. , Schreiber Lukas , Weder Christoph 
Published: February 2021

AbstractMost of the aerial organs of vascular plants are covered by a protective layer known as the cuticle, the main purpose of which is to limit transpirational water loss. Cuticles consist of an amphiphilic polyester matrix, polar polysaccharides that extend from the underlying epidermal cell wall and become less prominent towards the exterior, and hydrophobic waxes that dominate the surface. Here we report that the polarity gradient caused by this architecture renders the transport of water through astomatous olive and ivy leaf cuticles directional and that the permeation is regulated by the hydration level of the cutin-rich outer cuticular layer. We further report artificial nanocomposite membranes that are inspired by the cuticles’ compositionally graded architecture and consist of hydrophilic cellulose nanocrystals and a hydrophobic polymer. The structure and composition of these cuticle-inspired membranes can easily be varied and this enables a systematic investigation of the water transport mechanism.
Power sector investment implications of climate impacts on renewable resources in Latin America and the Caribbean
Authors: Santos da Silva Silvia R. , Hejazi Mohamad I. , Iyer Gokul , Wild Thomas B. , Binsted Matthew , Miralles-Wilhelm Fernando , Patel Pralit , Snyder Abigail C. , Vernon Chris R. 
Published: February 2021

AbstractClimate change mitigation will require substantial investments in renewables. In addition, climate change will affect future renewable supply and hence, power sector investment requirements. We study the implications of climate impacts on renewables for power sector investments under deep decarbonization using a global integrated assessment model. We focus on Latin American and Caribbean, an under-studied region but of great interest due to its strong role in international climate mitigation and vulnerability to climate change. We find that accounting for climate impacts on renewables results in significant additional investments ($12–114 billion by 2100 across Latin American countries) for a region with weak financial infrastructure. We also demonstrate that accounting for climate impacts only on hydropower—a primary focus of previous studies—significantly underestimates cumulative investments, particularly in scenarios with high intermittent renewable deployment. Our study underscores the importance of comprehensive analyses of climate impacts on renewables for improved energy planning.
Ocean fronts and eddies force atmospheric rivers and heavy precipitation in western North America
Authors: Liu Xue , Ma Xiaohui , Chang Ping , Jia Yinglai , Fu Dan , Xu Guangzhi , Wu Lixin , Saravanan R. , Patricola Christina M. 
Published: February 2021

AbstractAtmospheric rivers (ARs) are responsible for over 90% of poleward water vapor transport in the mid-latitudes and can produce extreme precipitation when making landfall. However, weather and climate models still have difficulty simulating and predicting landfalling ARs and associated extreme precipitation, highlighting the need to better understand AR dynamics. Here, using high-resolution climate models and observations, we demonstrate that mesoscale sea-surface temperature (SST) anomalies along the Kuroshio Extension can exert a remote influence on landfalling ARs and related heavy precipitation along the west coast of North America. Inclusion of mesoscale SST forcing in the simulations results in approximately a 40% increase in landfalling ARs and up to a 30% increase in heavy precipitation in mountainous regions and this remote impact occurs on two-week time scales. The asymmetrical response of the atmosphere to warm vs. cold mesoscale SSTs over the eddy-rich Kuroshio Extension region is proposed as a forcing mechanism that results in a net increase of moisture flux above the planetary boundary layer, prompting AR genesis via enhancing moisture transport into extratropical cyclones in the presence of mesoscale SST forcing.
The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation
Authors: Minns Danielle , Smith Katie J. , Alessandrini Virginia , Hardisty Gareth , Melrose Lauren , Jackson-Jones Lucy , MacDonald Andrew S. , Davidson Donald J. , Gwyer Findlay Emily 
Published: February 2021

AbstractThe host defence peptide cathelicidin (LL-37 in humans, mCRAMP in mice) is released from neutrophils by de-granulation, NETosis and necrotic death; it has potent anti-pathogen activity as well as being a broad immunomodulator. Here we report that cathelicidin is a powerful Th17 potentiator which enhances aryl hydrocarbon receptor (AHR) and RORγt expression, in a TGF-β1-dependent manner. In the presence of TGF-β1, cathelicidin enhanced SMAD2/3 and STAT3 phosphorylation, and profoundly suppressed IL-2 and T-bet, directing T cells away from Th1 and into a Th17 phenotype. Strikingly, Th17, but not Th1, cells were protected from apoptosis by cathelicidin. We show that cathelicidin is released by neutrophils in mouse lymph nodes and that cathelicidin-deficient mice display suppressed Th17 responses during inflammation, but not at steady state. We propose that the neutrophil cathelicidin is required for maximal Th17 differentiation, and that this is one method by which early neutrophilia directs subsequent adaptive immune responses.
Accurate imputation of human leukocyte antigens with CookHLA
Authors: Cook Seungho , Choi Wanson , Lim Hyunjoon , Luo Yang , Kim Kunhee , Jia Xiaoming , Raychaudhuri Soumya , Han Buhm 
Published: February 2021

AbstractThe recent development of imputation methods enabled the prediction of human leukocyte antigen (HLA) alleles from intergenic SNP data, allowing studies to fine-map HLA for immune phenotypes. Here we report an accurate HLA imputation method, CookHLA, which has superior imputation accuracy compared to previous methods. CookHLA differs from other approaches in that it locally embeds prediction markers into highly polymorphic exons to account for exonic variability, and in that it adaptively learns the genetic map within MHC from the data to facilitate imputation. Our benchmarking with real datasets shows that our method achieves high imputation accuracy in a wide range of scenarios, including situations where the reference panel is small or ethnically unmatched.