bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel fusion protein TBLR1-RARα acts as an oncogene to induce murine promyelocytic leukemia: identification and treatment strategies
Authors: Li Shouyun , Yang Xue , Liu Shuang , Chen Yirui , Xing Haiyan , Tang Kejing , Tian Zheng , Xu Yingxi , Rao Qing , Wang Min , Wang Jianxiang 
Published: June 2021

AbstractAcute promyelocytic leukemia (APL) is characterized by a specific chromosome translocation involving RARα and its fusion partners. For decades, the advent of all-trans retinoic acid (ATRA) synergized with arsenic trioxide (As2O3) has turned most APL from highly fatal to highly curable. TBLR1-RARα (TR) is the tenth fusion gene of APL identified in our previous study, with its oncogenic role in the pathogenesis of APL not wholly unraveled. In this study, we found the expression of TR in mouse hematopoietic progenitors induces blockade of differentiation with enhanced proliferative capacity in vitro. A novel murine transplantable leukemia model was then established by expressing TR fusion gene in lineage-negative bone marrow mononuclear cells. Characteristics of primary TR mice revealed a rapid onset of aggressive leukemia with bleeding diathesis, which recapitulates human APL more accurately than other models. Despite the in vitro sensitivity to ATRA-induced cell differentiation, neither ATRA monotherapy nor combination with As2O3 confers survival benefit to TR mice, consistent with poor clinical outcome of APL patients with TR fusion gene. Based on histone deacetylation phenotypes implied by bioinformatic analysis, HDAC inhibitors demonstrated significant survival superiority in the survival of TR mice, yielding insights into clinical efficacy against rare types of APL.
Neutrophil extracellular traps impair intestinal barrier functions in sepsis by regulating TLR9-mediated endoplasmic reticulum stress pathway
Authors: Sun Shilong , Duan Zehua , Wang Xinyu , Chu Chengnan , Yang Chao , Chen Fang , Wang Daojuan , Wang Chenyang , Li Qiurong , Ding Weiwei 
Published: June 2021

AbstractIncreased neutrophil extracellular traps (NETs) formation has been found to be associated with intestinal inflammation, and it has been reported that NETs may drive the progression of gut dysregulation in sepsis. However, the biological function and regulation of NETs in sepsis-induced intestinal barrier dysfunction are not yet fully understood. First, we found that both circulating biomarkers of NETs and local NETs infiltration in the intestine were significantly increased and had positive correlations with markers of enterocyte injury in abdominal sepsis patients. Moreover, the levels of local citrullinated histone 3 (Cit H3) expression were associated with the levels of BIP expression. To further confirm the role of NETs in sepsis-induced intestinal injury, we compared peptidylarginine deiminase 4 (PAD4)-deficient mice and wild-type (WT) mice in a lethal septic shock model. In WT mice, the Cit H3-DNA complex was markedly increased, and elevated intestinal inflammation and endoplasmic reticulum (ER) stress activation were also found. Furthermore, PAD4 deficiency alleviated intestinal barrier disruption and decreased ER stress activation. Notably, NETs treatment induced intestinal epithelial monolayer barrier disruption and ER stress activation in a dose-dependent manner in vitro, and ER stress inhibition markedly attenuated intestinal apoptosis and tight junction injury. Finally, TLR9 antagonist administration significantly abrogated NETs-induced intestinal epithelial cell death through ER stress inhibition. Our results indicated that NETs could contribute to sepsis-induced intestinal barrier dysfunction by promoting inflammation and apoptosis. Suppression of the TLR9–ER stress signaling pathway can ameliorate NETs-induced intestinal epithelial cell death.
Mortalin/glucose-regulated protein 75 promotes the cisplatin-resistance of gastric cancer via regulating anti-oxidation/apoptosis and metabolic reprogramming
Authors: Dai Yi , Li Fan , Jiao Yuwen , Wang Guoguang , Zhan Tian , Xia Yunwei , Liu Hanyang , Yang Haojun , Zhang Jianping , Tang Liming 
Published: June 2021

AbstractPlatinum drug treatment is one of the most predominant chemotherapeutic strategies for patients with gastric cancer (GC). However, the therapeutic effect is less than satisfactory, largely due to the acquired resistance to platinum drugs. Therefore, a better understanding of the underlying mechanisms can greatly improve the therapeutic efficacy of GC. In this study, we aimed to investigate the chemo-resistance related functions/mechanisms and clinical significance of glucose-regulated protein 75 (GRP75) in GC. Here, our data showed that compared with SGC7901 cells, the expression of GRP75 was markedly higher in cisplatin-resistance cells (SGC7901CR). Knockdown of GRP75 abolished the maintenance of mitochondrial membrane potential (MMP) and inhibited the nuclear factor erythroid-2-related factor 2 (NRF2), phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), hypoxia-inducible factor 1α (HIF-1α), and c-myc, which resulted in blocking the activation of their downstream targets. These processes attenuated the anti-oxidation/apoptosis abilities and altered the metabolic reprogramming in SGC7901CRcells, leading to re-sensitizing these cells to cisplatin. However, overexpression of GRP75 in SGC7901 cells caused the opposite effects. A xenografts model confirmed the abovementioned results. In GC patients receiving platinum chemotherapy and a meta-analysis, a high level of GRP75 was positively associated with aggressive characteristics and poor prognosis including but not limited to gastrointestinal cancers, and was an independent predictor for overall survival. Collectively, our study indicated that GRP75 was involved in the cisplatin-resistance of GC and that GRP75 could be a potential therapeutic target for restoring the drug response in platinum-resistance cells and a useful additive prognostic tool in guiding clinical management of GC patients.
Solid-state nanopore systems: from materials to applications
Authors: He Yuhui , Tsutsui Makusu , Zhou Yue , Miao Xiang-Shui 
Published: June 2021

AbstractIon transport and hydrodynamic flow through nanometer-sized channels (nanopores) have been increasingly studied owing to not only the fundamental interest in the abundance of novel phenomena that has been observed but also their promising application in innovative nanodevices, including next-generation sequencers, nanopower generators, and memristive synapses. We first review various kinds of materials and the associated state-of-the-art processes developed for fabricating nanoscale pores, including the emerging structures of DNA origami and 2-dimensional nanopores. Then, the unique transport phenomena are examined wherein the surface properties of wall materials play predominant roles in inducing intriguing characteristics, such as ion selectivity and reverse electrodialysis. Finally, we highlight recent progress in the potential application of nanopores, ranging from their use in biosensors to nanopore-based artificial synapses.
Construction of C-C bonds via photoreductive coupling of ketones and aldehydes in the metal-organic-framework MFM-300(Cr)
Authors: Luo Tian , Li Lili , Chen Yinlin , An Jie , Liu Chengcheng , Yan Zheng , Carter Joseph H. , Han Xue , Sheveleva Alena M. , Tuna Floriana , McInnes Eric J. L. , Tang Chiu C. , Schröder Martin , Yang Sihai 
Published: June 2021

AbstractConstruction of C-C bonds via reductive coupling of aldehydes and ketones is hindered by the highly negative reduction potential of these carbonyl substrates, particularly ketones, and this renders the formation of ketyl radicals extremely endergonic. Here, we report the efficient activation of carbonyl compounds by the formation of specific host-guest interactions in a hydroxyl-decorated porous photocatalyst. MFM-300(Cr) exhibits a band gap of 1.75 eV and shows excellent catalytic activity and stability towards the photoreductive coupling of 30 different aldehydes and ketones to the corresponding 1,2-diols at room temperature. Synchrotron X-ray diffraction and electron paramagnetic resonance spectroscopy confirm the generation of ketyl radicals via confinement within MFM-300(Cr). This protocol removes simultaneously the need for a precious metal-based photocatalyst or for amine-based sacrificial agents for the photochemical synthesis.
Evidence of the interplay of genetics and culture in Ethiopia
Authors: López Saioa , Tarekegn Ayele , Band Gavin , van Dorp Lucy , Bird Nancy , Morris Sam , Oljira Tamiru , Mekonnen Ephrem , Bekele Endashaw , Blench Roger , Thomas Mark G. , Bradman Neil , Hellenthal Garrett 
Published: June 2021

AbstractThe rich linguistic, ethnic and cultural diversity of Ethiopia provides an unprecedented opportunity to understand the level to which cultural factors correlate with–and shape–genetic structure in human populations. Using primarily new genetic variation data covering 1,214 Ethiopians representing 68 different ethnic groups, together with information on individuals’ birthplaces, linguistic/religious practices and 31 cultural practices, we disentangle the effects of geographic distance, elevation, and social factors on the genetic structure of Ethiopians today. We provide evidence of associations between social behaviours and genetic differences among present-day peoples. We show that genetic similarity is broadly associated with linguistic affiliation, but also identify pronounced genetic similarity among groups from disparate language classifications that may in part be attributable to recent intermixing. We also illustrate how groups reporting the same culture traits are more genetically similar on average and show evidence of recent intermixing, suggesting that shared cultural traits may promote admixture. In addition to providing insights into the genetic structure and history of Ethiopia, we identify the most important cultural and geographic predictors of genetic differentiation and provide a resource for designing sampling protocols for future genetic studies involving Ethiopians.
Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens
Authors: Crowe-McAuliffe Caillan , Murina Victoriia , Turnbull Kathryn Jane , Kasari Marje , Mohamad Merianne , Polte Christine , Takada Hiraku , Vaitkevicius Karolis , Johansson Jörgen , Ignatova Zoya , Atkinson Gemma C. , O’Neill Alex J. , Hauryliuk Vasili , Wilson Daniel N. 
Published: June 2021

AbstractTarget protection proteins confer resistance to the host organism by directly binding to the antibiotic target. One class of such proteins are the antibiotic resistance (ARE) ATP-binding cassette (ABC) proteins of the F-subtype (ARE-ABCFs), which are widely distributed throughout Gram-positive bacteria and bind the ribosome to alleviate translational inhibition from antibiotics that target the large ribosomal subunit. Here, we present single-particle cryo-EM structures of ARE-ABCF-ribosome complexes from three Gram-positive pathogens: Enterococcus faecalis LsaA, Staphylococcus haemolyticus VgaALC and Listeria monocytogenes VgaL. Supported by extensive mutagenesis analysis, these structures enable a general model for antibiotic resistance mediated by these ARE-ABCFs to be proposed. In this model, ABCF binding to the antibiotic-stalled ribosome mediates antibiotic release via mechanistically diverse long-range conformational relays that converge on a few conserved ribosomal RNA nucleotides located at the peptidyltransferase center. These insights are important for the future development of antibiotics that overcome such target protection resistance mechanisms.
Optoregulated force application to cellular receptors using molecular motors
Authors: Zheng Yijun , Han Mitchell K. L. , Zhao Renping , Blass Johanna , Zhang Jingnan , Zhou Dennis W. , Colard-Itté Jean-Rémy , Dattler Damien , Çolak Arzu , Hoth Markus , García Andrés J. , Qu Bin , Bennewitz Roland , Giuseppone Nicolas , del Campo Aránzazu 
Published: June 2021

AbstractProgress in our understanding of mechanotransduction events requires noninvasive methods for the manipulation of forces at molecular scale in physiological environments. Inspired by cellular mechanisms for force application (i.e. motor proteins pulling on cytoskeletal fibers), we present a unique molecular machine that can apply forces at cell-matrix and cell-cell junctions using light as an energy source. The key actuator is a light-driven rotatory molecular motor linked to polymer chains, which is intercalated between a membrane receptor and an engineered biointerface. The light-driven actuation of the molecular motor is converted in mechanical twisting of the entangled polymer chains, which will in turn effectively “pull” on engaged cell membrane receptors (e.g., integrins, T cell receptors) within the illuminated area. Applied forces have physiologically-relevant magnitude and occur at time scales within the relevant ranges for mechanotransduction at cell-friendly exposure conditions, as demonstrated in force-dependent focal adhesion maturation and T cell activation experiments. Our results reveal the potential of nanomotors for the manipulation of living cells at the molecular scale and demonstrate a functionality which at the moment cannot be achieved by other technologies for force application.
Overexpression of human BAG3P209L in mice causes restrictive cardiomyopathy
Authors: Kimura Kenichi , Ooms Astrid , Graf-Riesen Kathrin , Kuppusamy Maithreyan , Unger Andreas , Schuld Julia , Daerr Jan , Lother Achim , Geisen Caroline , Hein Lutz , Takahashi Satoru , Li Guang , Röll Wilhelm , Bloch Wilhelm , van der Ven Peter F. M. , Linke Wolfgang A. , Wu Sean M. , Huesgen Pitter F. , Höhfeld Jörg , Fürst Dieter O. , Fleischmann Bernd K. , Hesse Michael 
Published: June 2021

AbstractAn amino acid exchange (P209L) in the HSPB8 binding site of the human co-chaperone BAG3 gives rise to severe childhood cardiomyopathy. To phenocopy the disease in mice and gain insight into its mechanisms, we generated humanized transgenic mouse models. Expression of human BAG3P209L-eGFP in mice caused Z-disc disintegration and formation of protein aggregates. This was accompanied by massive fibrosis resulting in early-onset restrictive cardiomyopathy with increased mortality as observed in patients. RNA-Seq and proteomics revealed changes in the protein quality control system and increased autophagy in hearts from hBAG3P209L-eGFP mice. The mutation renders hBAG3P209L less soluble in vivo and induces protein aggregation, but does not abrogate hBAG3 binding properties. In conclusion, we report a mouse model mimicking the human disease. Our data suggest that the disease mechanism is due to accumulation of hBAG3P209L and mouse Bag3, causing sequestering of components of the protein quality control system and autophagy machinery leading to sarcomere disruption.
Family history of early onset acute lymphoblastic leukemia is suggesting genetic associations
Authors: Li Xinjun , Sundquist Kristina , Sundquist Jan , Försti Asta , Hemminki Kari 
Published: June 2021

AbstractChildhood acute lymphoblastic leukemia (ALL) has an origin in the fetal period which may distinguish it from ALL diagnosed later in life. We wanted to test whether familial risks differ in ALL diagnosed in the very early childhood from ALL diagnosed later. The Swedish nation-wide family-cancer data were used until year 2016 to calculate standardized incidence ratios (SIRs) for familial risks in ALL in three diagnostic age-groups: 0–4, 5–34 and 35 + years. Among 1335 ALL patients diagnosed before age 5, familial risks were increased for esophageal (4.78), breast (1.42), prostate (1.40) and connective tissue (2.97) cancers and leukemia (2.51, ALL 7.81). In age-group 5–34 years, rectal (1.73) and endometrial (2.40) cancer, myeloma (2.25) and leukemia (2.00, ALL 4.60) reached statistical significance. In the oldest age-group, the only association was with Hodgkin lymphoma (3.42). Diagnostic ages of family members of ALL patients were significantly lower compared to these cancers in the population for breast, prostate and rectal cancers. The patterns of increased familial cancers suggest that BRCA2 mutations could contribute to associations of ALL with breast and prostate cancers, and mismatch gene PMS2 mutations with rectal and endometrial cancers. Future DNA sequencing data will be a test for these familial predictions.
Comparison of the fertility of tumor suppressor gene-deficient C57BL/6 mouse strains reveals stable reproductive aging and novel pleiotropic gene
Authors: Kohzaki Masaoki , Ootsuyama Akira , Umata Toshiyuki , Okazaki Ryuji 
Published: June 2021

AbstractTumor suppressor genes are involved in maintaining genome integrity during reproduction (e.g., meiosis). Thus, deleterious alleles in tumor suppressor-deficient mice would exhibit higher mortality during the perinatal period. A recent aging model proposes that perinatal mortality and age-related deleterious changes might define lifespan. This study aimed to quantitatively understand the relationship between reproduction and lifespan using three established tumor suppressor gene (p53, APC, and RECQL4)-deficient mouse strains with the same C57BL/6 background. Transgenic mice delivered slightly reduced numbers of 1st pups than wild-type mice [ratio: 0.81–0.93 (p = 0.1–0.61)] during a similar delivery period, which suggest that the tumor suppressor gene-deficient mice undergo relatively stable reproduction. However, the transgenic 1st pups died within a few days after birth, resulting in a further reduction in litter size at 3 weeks after delivery compared with that of wild-type mice [ratio: 0.35–0.68 (p = 0.034–0.24)] without sex differences, although the lifespan was variable. Unexpectedly, the significance of reproductive reduction in transgenic mice was decreased at the 2nd or later delivery. Because mice are easily affected by environmental factors, our data underscore the importance of defining reproductive ability through experiments on aging-related reproduction that can reveal a trade-off between fecundity and aging and identify RECQL4 as a novel pleiotropic gene.
The potential of adoptive transfer of γ9δ2 T cells to enhance blinatumomab’s antitumor activity against B-cell malignancy
Authors: Chen Yun-Hsiang , Wang Yun , Liao Cheng-Hao , Hsu Shu-Ching 
Published: June 2021

AbstractBlinatumomab, a bispecific T cell engager (BiTE) antibody targeting CD19 and CD3ε, can redirect T cells toward CD19-positive tumor cells and has been approved to treat relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). However, chemotherapeutic regimens can severely reduce T cells’ number and cytotoxic function, leading to an inadequate response to blinatumomab treatment in patients. In addition, it was reported that a substantial portion of R/R B-ALL patients failing blinatumomab treatment had the extramedullary disease, indicating the poor ability of blinatumomab in treating extramedullary disease. In this study, we investigated whether the adoptive transfer of ex vivo expanded γ9δ2 T cells could act as the effector of blinatumomab to enhance blinatumomab’s antitumor activity against B-cell malignancies in vivo. Repeated infusion of blinatumomab and human γ9δ2 T cells led to more prolonged survival than that of blinatumomab or human γ9δ2 T cells alone in the mice xenografted with Raji cells. Furthermore, adoptive transfer of γ9δ2 T cells reduced tumor mass outside the bone marrow, indicating the potential of γ9δ2 T cells to eradicate the extramedullary disease. Our results suggest that the addition of γ9δ2 T cells to the blinatumomab treatment regimens could be an effective approach to enhancing blinatumomab’s therapeutic efficacy. The concept of this strategy may also be applied to other antigen-specific BiTE therapies for other malignancies.
A lossless compression method for multi-component medical images based on big data mining
Authors: Xin Gangtao , Fan Pingyi 
Published: June 2021

AbstractIn disease diagnosis, medical image plays an important part. Its lossless compression is pretty critical, which directly determines the requirement of local storage space and communication bandwidth of remote medical systems, so as to help the diagnosis and treatment of patients. There are two extraordinary properties related to medical images: lossless and similarity. How to take advantage of these two properties to reduce the information needed to represent an image is the key point of compression. In this paper, we employ the big data mining to set up the image codebook. That is, to find the basic components of images. We propose a soft compression algorithm for multi-component medical images, which can exactly reflect the fundamental structure of images. A general representation framework for image compression is also put forward and the results indicate that our developed soft compression algorithm can outperform the popular benchmarks PNG and JPEG2000 in terms of compression ratio.
Interaction between damping characteristics and the initial‐stage short‐circuit current of MMC‐HVDC transmission systems
Authors: Qin Boyu , Liu Wansong , Zhou Xingyue , Ding Tao , Li Wei , Zomaya Albert Y. 
Published: June 2021

AbstractThis paper studies the interaction between the damping characteristics and the initial‐stage short‐circuit current of modular multilevel converter based high voltage direct current (MMC‐HVDC) transmission system. First, the MMCs' input–output characteristics are obtained through the operator approach, and the influences of both linear part and nonlinear part are analysed. Second, an input–output characteristics based short‐circuit current calculation method is proposed. Third, an eigenvalue‐based comprehensive index is proposed to evaluate the damping characteristics of the MMC‐HVDC transmission system. Finally, the interaction between the damping characteristics and the initial‐stage DC short‐circuit current is analysed under different system parameters and DC system structures. The analysis results show that there is a negative correlation between the system damping characteristics and the average rising rate of the short‐circuit current. The proposed index G can effectively evaluate the short‐circuit current of MMC‐HVDC and can provide guidance for the planning of DC system structure, the selection of operation mode and system parameters.
A transformerless active voltage quality regulator with the novel three‐leg circuit
Authors: Wang Sen , Pei Yunqing , Rong Weiqing , Xiao Guochun , Huang Jingjing , Zhang Jialei 
Published: June 2021

AbstractVoltage sags and momentary interruptions of power are the most severe voltage disturbances. Here, a tansformerless active voltage quality regulator with the novel three‐leg circuit is proposed to mitigate long duration and deep voltage sags. The shunt rectifier and series inverter of this novel three‐leg circuit are all full‐bridge structures, so it has lower DC bus voltage and smaller filter parameters than the conventional half‐bridge topologies. The totem‐pole bridgeless boost circuit is formed among the three bridge arms and the DC bus voltage will be charged to exceed the peak value of the supply voltage. It can compensate for deep voltage sags (that may be more than 50% of the nominal voltage). Compared to the conventional transformerless series‐connected topology, the proposed topology has the merits of higher efficiency, smaller volume and lower cost. The validity and feasibility of the proposed topology are verified by theoretical analysis, simulation and experiment.