bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interplay between transforming growth factor-β and Nur77 in dual regulations of inhibitor of differentiation 1 for colonic tumorigenesis
Authors: Niu Boning , Liu Jie , Lv Ben , Lin Jiacheng , Li Xin , Wu Chunxiao , Jiang Xiaohua , Zeng Zhiping , Zhang Xiao-kun , Zhou Hu 
Published: May 2021

AbstractThe paradoxical roles of transforming growth factor-β (TGFβ) signaling and nuclear receptor Nur77 in colon cancer development are known but the underlying mechanisms remain obscure. Inhibitor of differentiation 1 (ID1) is a target gene of TGFβ and a key promoter for colon cancer progression. Here, we show that Nur77 enhances TGFβ/Smad3-induced ID1 mRNA expression through hindering Smurf2-mediated Smad3 mono-ubiquitylation, resulting in ID1 upregulation. In the absence of TGFβ, however, Nur77 destabilizes ID1 protein by promoting Smurf2-mediated ID1 poly-ubiquitylation, resulting in ID1 downregulation. Interestingly, TGFβ stabilizes ID1 protein by switching Nur77 interaction partners to inhibit ID1 ubiquitylation. This also endows TGFβ with an active pro-tumorigenic action in Smad4-deficient colon cancers. Thus, TGFβ converts Nur77’s role from destabilizing ID1 protein and cancer inhibition to inducing ID1 mRNA expression and cancer promotion, which is highly relevant to colon cancer stemness, metastasis and oxaliplatin resistance. Our data therefore define the integrated duality of Nur77 and TGFβ signaling in regulating ID1 expression and provide mechanistic insights into the paradoxical roles of TGFβ and Nur77 in colon cancer progression.
Structure-based engineering of substrate specificity for pinoresinol-lariciresinol reductases
Authors: Xiao Ying , Shao Kai , Zhou Jingwen , Wang Lian , Ma Xueqi , Wu Di , Yang Yingbo , Chen Junfeng , Feng Jingxian , Qiu Shi , Lv Zongyou , Zhang Lei , Zhang Peng , Chen Wansheng 
Published: May 2021

AbstractPinoresinol–lariciresinol reductases (PLRs) are enzymes involved in the lignan biosynthesis after the initial dimerization of two monolignols, and this represents the entry point for the synthesis of 8-8′ lignans and contributes greatly to their structural diversity. Of particular interest has been the determination of how differing substrate specificities are achieved with these enzymes. Here, we present crystal structures of IiPLR1 from Isatis indigotica and pinoresinol reductases (PrRs) AtPrR1 and AtPrR2 from Arabidopsis thaliana, in the apo, substrate-bound and product-bound states. Each structure contains a head-to-tail homodimer, and the catalytic pocket comprises structural elements from both monomers. β4 loop covers the top of the pocket, and residue 98 from the loop governs catalytic specificity. The substrate specificities of IiPLR1 and AtPrR2 can be switched via structure-guided mutagenesis. Our study provides insight into the molecular mechanism underlying the substrate specificity of PLRs/PrRs and suggests an efficient strategy for the large-scale commercial production of the pharmaceutically valuable compound lariciresinol.
Clonal evolution and clinical implications of genetic abnormalities in blastic transformation of chronic myeloid leukaemia
Authors: Ochi Yotaro , Yoshida Kenichi , Huang Ying-Jung , Kuo Ming-Chung , Nannya Yasuhito , Sasaki Ko , Mitani Kinuko , Hosoya Noriko , Hiramoto Nobuhiro , Ishikawa Takayuki , Branford Susan , Shanmuganathan Naranie , Ohyashiki Kazuma , Takahashi Naoto , Takaku Tomoiku , Tsuchiya Shun , Kanemura Nobuhiro , Nakamura Nobuhiko , Ueda Yasunori , Yoshihara Satoshi , Bera Rabindranath , Shiozawa Yusuke , Zhao Lanying , Takeda June , Watatani Yosaku , Okuda Rurika , Makishima Hideki , Shiraishi Yuichi , Chiba Kenichi , Tanaka Hiroko , Sanada Masashi , Takaori-Kondo Akifumi , Miyano Satoru , Ogawa Seishi , Shih Lee-Yung 
Published: May 2021

AbstractBlast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.
Revealing pseudorotation and ring-opening reactions in colloidal organic molecules
Authors: Swinkels P. J. M. , Stuij S. G. , Gong Z. , Jonas H. , Ruffino N. , Linden B. van der , Bolhuis P. G. , Sacanna S. , Woutersen S. , Schall P. 
Published: May 2021

AbstractColloids have a rich history of being used as ‘big atoms’ mimicking real atoms to study crystallization, gelation and the glass transition of condensed matter. Emulating the dynamics of molecules, however, has remained elusive. Recent advances in colloid chemistry allow patchy particles to be synthesized with accurate control over shape, functionality and coordination number. Here, we show that colloidal alkanes, specifically colloidal cyclopentane, assembled from tetrameric patchy particles by critical Casimir forces undergo the same chemical transformations as their atomic counterparts, allowing their dynamics to be studied in real time. We directly observe transitions between chair and twist conformations in colloidal cyclopentane, and we elucidate the interplay of bond bending strain and entropy in the molecular transition states and ring-opening reactions. These results open the door to investigate complex molecular kinetics and molecular reactions in the high-temperature classical limit, in which the colloidal analogue becomes a good model.
Discovery of first-in-class inhibitors of ASH1L histone methyltransferase with anti-leukemic activity
Authors: Rogawski David S. , Deng Jing , Li Hao , Miao Hongzhi , Borkin Dmitry , Purohit Trupta , Song Jiho , Chase Jennifer , Li Shuangjiang , Ndoj Juliano , Klossowski Szymon , Kim EunGi , Mao Fengbiao , Zhou Bo , Ropa James , Krotoska Marta Z. , Jin Zhuang , Ernst Patricia , Feng Xiaomin , Huang Gang , Nishioka Kenichi , Kelly Samantha , He Miao , Wen Bo , Sun Duxin , Muntean Andrew , Dou Yali , Maillard Ivan , Cierpicki Tomasz , Grembecka Jolanta 
Published: May 2021

AbstractASH1L histone methyltransferase plays a crucial role in the pathogenesis of different diseases, including acute leukemia. While ASH1L represents an attractive drug target, developing ASH1L inhibitors is challenging, as the catalytic SET domain adapts an inactive conformation with autoinhibitory loop blocking the access to the active site. Here, by applying fragment-based screening followed by medicinal chemistry and a structure-based design, we developed first-in-class small molecule inhibitors of the ASH1L SET domain. The crystal structures of ASH1L-inhibitor complexes reveal compound binding to the autoinhibitory loop region in the SET domain. When tested in MLL leukemia models, our lead compound, AS-99, blocks cell proliferation, induces apoptosis and differentiation, downregulates MLL fusion target genes, and reduces the leukemia burden in vivo. This work validates the ASH1L SET domain as a druggable target and provides a chemical probe to further study the biological functions of ASH1L as well as to develop therapeutic agents.
Visible colorimetric dosimetry of UV and ionizing radiations by a dual-module photochromic nanocluster
Authors: Lu Huangjie , Xie Jian , Wang Xin-Yu , Wang Yaxing , Li Zi-Jian , Diefenbach Kariem , Pan Qing-Jiang , Qian Yuan , Wang Jian-Qiang , Wang Shuao , Lin Jian 
Published: May 2021

AbstractRadiation dosimeters displaying conspicuous response of irradiance are highly desirable, owing to the growing demand of monitoring high-energy radiation and environmental exposure. Herein, we present a case of dosimetry based on a discrete nanocluster, [Th6(OH)4(O)4(H2O)6](TPC)8(HCOO)4∙4DMF∙H2O (Th-SINAP-100), by judiciously incorporating heavy Th6 polynuclear centers as radiation attenuator and organic linkers as photo-responsive sensor. Interestingly, dual-module photochromic transitions upon multiple external stimuli including UV, β-ray, and γ-ray are integrated into this single material. The striking color change, and more significantly, the visible color transition of luminescence in response to accumulating radiation dose allow an on-site quantitative platform for naked-eye detection of ionization radiations over a broad range (1–80 kGy). Single crystal X-ray diffraction and density functional theory calculations reveal that the dual-module photochromism can be attributed to the π(TPC) → π*(TPC) intermolecular charge transfer driven by enhanced π-π stacking interaction between the adjacent TPC moieties upon irradiation.
Potential changes in the connectivity of marine protected areas driven by extreme ocean warming
Authors: Lima Luciana Shigihara , Gherardi Douglas Francisco Marcolino , Pezzi Luciano Ponzi , Passos Leilane Gonçalves dos , Endo Clarissa Akemi Kajiya , Quimbayo Juan Pablo 
Published: May 2021

AbstractProjected future climate scenarios anticipate a warmer tropical ocean and changes in surface currents that will likely influence the survival of marine organisms and the connectivity of marine protected areas (MPAs) networks. We simulated the regional effects of climate change on the demographic connectivity of parrotfishes in nine MPAs in the South Atlantic through downscaling of the HadGEM2-ES Earth System Model running the RCP 8.5 greenhouse gas trajectory. Results indicate a tropicalization scenario over the tropical southwest Atlantic following an increase of sea surface temperature (SST) between 1.8 and 4.5 °C and changes in mean surface currents between − 0.6 to 0.5 m s−1relative to present conditions. High mortality rates will reduce demographic connectivity and increase the isolation of oceanic islands. The simulation of organismal response to ocean warming shows that acclimation can significantly improve (p < 0.001) particle survival, promoting connectivity and tropicalization of MPAs, with potential impacts on their functional integrity and long-term resilience.
The durability of flexible eddy current array (FECA) sensors in harsh service environments
Authors: Song Yujian , Chen Tao , Cui Ronghong , He Yuting , Fan Xianghong , Ma Binlin 
Published: May 2021

AbstractSensors for structural health monitoring (SHM) need to be permanently integrated on structures and withstand the harsh service environments, which has been a big challenge for the application of SHM in aircrafts. This paper focuses on the durability of flexible eddy current array (FECA) sensors in harsh service environments of aircrafts, including vibration environment and several typical exposed environments. First, a kind of FECA sensor is illustrated and its integration method is proposed. Moreover, in order to study the durability of the sensor in vibration environment, the modal analysis is performed by the finite element method. According to the simulation results, the durability experiment in vibration environment is carried out under the fourth order vibration mode, which makes the sensor suffer the harshest vibration loads. During the vibration experiment, output signals of the sensor keep stable and the sensor is well bonded to the structure, which shows the integrated sensor has high durability in vibration environment. Finally, the durability of integrated sensors is separately tested in three exposed environments, including salt fog corrosion environment, fluid immersion environment, as well as hygrothermal and ultraviolet-radiation environment. After these environmental exposure experiments, all sensors are well bonded to structures and can effectively monitor fatigue cracks, which shows great durability. Therefore, FECA sensors can survive in harsh service environments of aircrafts, which provides important support for the engineering applications of FECA sensors.
Sharp rises in large-scale, long-duration precipitation extremes with higher temperatures over Japan
Authors: Hatsuzuka Daisuke , Sato Tomonori , Higuchi Yoshihito 
Published: May 2021

AbstractThe intensity of extreme precipitation has been projected to increase with increasing air temperature according to the thermodynamic Clausius–Clapeyron (C-C) relation. Over the last decade, observational studies have succeeded in demonstrating the scaling relationship between extreme precipitation and temperature to understand the projected changes. In mid-latitude coastal regions, intense precipitation is strongly influenced by synoptic patterns and a particular characteristic is the long-lasting heavy precipitation driven by abundant moisture transport. However, the effect of synoptic patterns on the scaling relationship remains unclear. Here we conduct an event-based analysis using long-term historical records in Japan, to distinguish extreme precipitation arising from different synoptic patterns. We find that event peak intensity increases more sharply in persistent precipitation events, which lasted more than 10 h, sustained by atmospheric river-like circulation patterns. The long duration-accumulated precipitation extremes also increase with temperature at a rate considerably above the C-C rate at higher temperatures. Our result suggests that long-lasting precipitation events respond more to warming compared with short-duration events. This greatly increases the risks of future floods and landslides in the mid-latitude coastal regions.
Deep learning for diagnosis of acute promyelocytic leukemia via recognition of genomically imprinted morphologic features
Authors: Sidhom John-William , Siddarthan Ingharan J. , Lai Bo-Shiun , Luo Adam , Hambley Bryan C. , Bynum Jennifer , Duffield Amy S. , Streiff Michael B. , Moliterno Alison R. , Imus Philip , Gocke Christian B. , Gondek Lukasz P. , DeZern Amy E. , Baras Alexander S. , Kickler Thomas , Levis Mark J. , Shenderov Eugene 
Published: May 2021

AbstractAcute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML), classified by a translocation between chromosomes 15 and 17 [t(15;17)], that is considered a true oncologic emergency though appropriate therapy is considered curative. Therapy is often initiated on clinical suspicion, informed by both clinical presentation as well as direct visualization of the peripheral smear. We hypothesized that genomic imprinting of morphologic features learned by deep learning pattern recognition would have greater discriminatory power and consistency compared to humans, thereby facilitating identification of t(15;17) positive APL. By applying both cell-level and patient-level classification linked to t(15;17) PML/RARA ground-truth, we demonstrate that deep learning is capable of distinguishing APL in both discovery and prospective independent cohort of patients. Furthermore, we extract learned information from the trained network to identify previously undescribed morphological features of APL. The deep learning method we describe herein potentially allows a rapid, explainable, and accurate physician-aid for diagnosing APL at the time of presentation in any resource-poor or -rich medical setting given the universally available peripheral smear.
Exploring the feasibility of using real-world data from a large clinical data research network to simulate clinical trials of Alzheimer’s disease
Authors: Chen Zhaoyi , Zhang Hansi , Guo Yi , George Thomas J. , Prosperi Mattia , Hogan William R. , He Zhe , Shenkman Elizabeth A. , Wang Fei , Bian Jiang 
Published: May 2021

AbstractIn this study, we explored the feasibility of using real-world data (RWD) from a large clinical research network to simulate real-world clinical trials of Alzheimer’s disease (AD). The target trial (i.e., NCT00478205) is a Phase III double-blind, parallel-group trial that compared the 23 mg donepezil sustained release with the 10 mg donepezil immediate release formulation in patients with moderate to severe AD. We followed the target trial’s study protocol to identify the study population, treatment regimen assignments and outcome assessments, and to set up a number of different simulation scenarios and parameters. We considered two main scenarios: (1) a one-arm simulation: simulating a standard-of-care (SOC) arm that can serve as an external control arm; and (2) a two-arm simulation: simulating both intervention and control arms with proper patient matching algorithms for comparative effectiveness analysis. In the two-arm simulation scenario, we used propensity score matching controlling for baseline characteristics to simulate the randomization process. In the two-arm simulation, higher serious adverse event (SAE) rates were observed in the simulated trials than the rates reported in original trial, and a higher SAE rate was observed in the 23 mg arm than in the 10 mg SOC arm. In the one-arm simulation scenario, similar estimates of SAE rates were observed when proportional sampling was used to control demographic variables. In conclusion, trial simulation using RWD is feasible in this example of AD trial in terms of safety evaluation. Trial simulation using RWD could be a valuable tool for post-market comparative effectiveness studies and for informing future trials’ design. Nevertheless, such an approach may be limited, for example, by the availability of RWD that matches the target trials of interest, and further investigations are warranted.
Non-quaternary oximes detoxify nerve agents and reactivate nerve agent-inhibited human butyrylcholinesterase
Authors: Amitai Gabriel , Plotnikov Alexander , Chapman Shira , Lazar Shlomi , Gez Rellie , Loewenthal Dan , Shurrush Khriesto A. , Cohen Galit , Solmesky Leonardo J. , Barr Haim , Russell Alan J. 
Published: May 2021

AbstractGovernment-sanctioned use of nerve agents (NA) has escalated dramatically in recent years. Oxime reactivators of organophosphate (OP)-inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) serve as antidotes toward poisoning by OPNAs. The oximes used as therapeutics are quaternary compounds that cannot penetrate the blood–brain barrier (BBB). There remains an urgent need for the development of next generation OPNA therapeutics. We have developed two high-throughput screening (HTS) assays using a fluorogenic NA surrogate, O-ethyl methylphosphonyl O-4-methyl-3-cyano-coumarin (EMP-MeCyC). EMP-MeCyC detoxification and EMP-BChE reactivation screening campaigns of ~155,000 small molecules resulted in the identification of 33 nucleophile candidates, including non-quaternary oximes. Four of the oximes were reactivators of both Sarin- and VX-inhibited BChE and directly detoxified Sarin. One oxime also detoxified VX. The novel reactivators included a non-quaternary pyridine amidoxime, benzamidoxime, benzaldoxime and a piperidyl-ketoxime. The VX-inhibited BChE reactivation reaction rates by these novel molecules were similar to those observed with known bis-quaternary reactivators and faster than mono-quaternary pyridinium oximes. Notably, we discovered the first ketoxime reactivator of OP-ChEs and detoxifier of OPNAs. Preliminary toxicological studies demonstrated that the newly discovered non-quaternary oximes were relatively non-toxic in mice. The discovery of unique non-quaternary oximes opens the door to the design of novel therapeutics and decontamination agents following OPNA exposure.
Oxygen tension modulates the mitochondrial genetic bottleneck and influences the segregation of a heteroplasmic mtDNA variant in vitro
Authors: Pezet Mikael G. , Gomez-Duran Aurora , Klimm Florian , Aryaman Juvid , Burr Stephen , Wei Wei , Saitou Mitinori , Prudent Julien , Chinnery Patrick F. 
Published: May 2021

AbstractMost humans carry a mixed population of mitochondrial DNA (mtDNA heteroplasmy) affecting ~1–2% of molecules, but rapid percentage shifts occur over one generation leading to severe mitochondrial diseases. A decrease in the amount of mtDNA within the developing female germ line appears to play a role, but other sub-cellular mechanisms have been implicated. Establishing an in vitro model of early mammalian germ cell development from embryonic stem cells, here we show that the reduction of mtDNA content is modulated by oxygen and reaches a nadir immediately before germ cell specification. The observed genetic bottleneck was accompanied by a decrease in mtDNA replicating foci and the segregation of heteroplasmy, which were both abolished at higher oxygen levels. Thus, differences in oxygen tension occurring during early development likely modulate the amount of mtDNA, facilitating mtDNA segregation and contributing to tissue-specific mutation loads.
Time-resolved spectroscopic and electrophysiological data reveal insights in the gating mechanism of anion channelrhodopsin
Authors: Dreier Max-Aylmer , Althoff Philipp , Norahan Mohamad Javad , Tennigkeit Stefan Alexander , El-Mashtoly Samir F. , Lübben Mathias , Kötting Carsten , Rudack Till , Gerwert Klaus 
Published: May 2021

AbstractChannelrhodopsins are widely used in optogenetic applications. High photocurrents and low current inactivation levels are desirable. Two parallel photocycles evoked by different retinal conformations cause cation-conducting channelrhodopsin-2 (CrChR2) inactivation: one with efficient conductivity; one with low conductivity. Given the longer half-life of the low conducting photocycle intermediates, which accumulate under continuous illumination, resulting in a largely reduced photocurrent. Here, we demonstrate that for channelrhodopsin-1 of the cryptophyte Guillardia theta (GtACR1), the highly conducting C = N-anti-photocycle was the sole operating cycle using time-resolved step-scan FTIR spectroscopy. The correlation between our spectroscopic measurements and previously reported electrophysiological data provides insights into molecular gating mechanisms and their role in the characteristic high photocurrents. The mechanistic importance of the central constriction site amino acid Glu-68 is also shown. We propose that canceling out the poorly conducting photocycle avoids the inactivation observed in CrChR2, and anticipate that this discovery will advance the development of optimized optogenetic tools.
A live imaging system to analyze spatiotemporal dynamics of RNA polymerase II modification in Arabidopsis thaliana
Authors: Shibuta Mio K. , Sakamoto Takuya , Yamaoka Tamako , Yoshikawa Mayu , Kasamatsu Shusuke , Yagi Noriyoshi , Fujimoto Satoru , Suzuki Takamasa , Uchino Satoshi , Sato Yuko , Kimura Hiroshi , Matsunaga Sachihiro 
Published: May 2021

AbstractSpatiotemporal changes in general transcription levels play a vital role in the dynamic regulation of various critical activities. Phosphorylation levels at Ser2 in heptad repeats within the C-terminal domain of RNA polymerase II, representing the elongation form, is an indicator of transcription. However, rapid transcriptional changes during tissue development and cellular phenomena are difficult to capture in living organisms. We introduced a genetically encoded system termed modification-specific intracellular antibody (mintbody) into Arabidopsis thaliana. We developed a protein processing- and 2A peptide-mediated two-component system for real-time quantitative measurement of endogenous modification level. This system enables quantitative tracking of the spatiotemporal dynamics of transcription. Using this method, we observed that the transcription level varies among tissues in the root and changes dynamically during the mitotic phase. The approach is effective for achieving live visualization of the transcription level in a single cell and facilitates an improved understanding of spatiotemporal transcription dynamics.