bluuebunny/crossref_metadata_2025_split huggingface dataset:
miR-181a initiates and perpetuates oncogenic transformation through the regulation of innate immune signaling
Authors: Knarr Matthew , Avelar Rita A. , Sekhar Sreeja C. , Kwiatkowski Lily J. , Dziubinski Michele L. , McAnulty Jessica , Skala Stephanie , Avril Stefanie , Drapkin Ronny , DiFeo Analisa 
Published: June 2020

AbstractGenomic instability (GI) predisposes cells to malignant transformation, however the molecular mechanisms that allow for the propagation of cells with a high degree of genomic instability remain unclear. Here we report that miR-181a is able to transform fallopian tube secretory epithelial cells through the inhibition of RB1 and stimulator-of-interferon-genes (STING) to propagate cells with a high degree of GI. MiR-181a targeting of RB1 leads to profound nuclear defects and GI generating aberrant cytoplasmic DNA, however simultaneous miR-181a mediated inhibition of STING allows cells to bypass interferon mediated cell death. We also found that high miR-181a is associated with decreased IFNγ response and lymphocyte infiltration in patient tumors. DNA oncoviruses are the only known inhibitors of STING that allow for cellular transformation, thus, our findings are the first to identify a miRNA that can downregulate STING expression to suppress activation of intrinsic interferon signaling. This study introduces miR-181a as a putative biomarker and identifies the miR-181a-STING axis as a promising target for therapeutic exploitation.
Focus on the spectra that matter by clustering of quantification data in shotgun proteomics
Authors: The Matthew , Käll Lukas 
Published: June 2020

AbstractIn shotgun proteomics, the analysis of label-free quantification experiments is typically limited by the identification rate and the noise level in the quantitative data. This generally causes a low sensitivity in differential expression analysis. Here, we propose a quantification-first approach for peptides that reverses the classical identification-first workflow, thereby preventing valuable information from being discarded in the identification stage. Specifically, we introduce a method, Quandenser, that applies unsupervised clustering on both MS1 and MS2 level to summarize all analytes of interest without assigning identities. This reduces search time due to the data reduction. We can now employ open modification and de novo searches to identify analytes of interest that would have gone unnoticed in traditional pipelines. Quandenser+Triqler outperforms the state-of-the-art method MaxQuant+Perseus, consistently reporting more differentially abundant proteins for all tested datasets. Software is available for all major operating systems at https://github.com/statisticalbiotechnology/quandenser, under Apache 2.0 license.
Groundwater level observations in 250,000 coastal US wells reveal scope of potential seawater intrusion
Authors: Jasechko Scott , Perrone Debra , Seybold Hansjörg , Fan Ying , Kirchner James W. 
Published: June 2020

AbstractSeawater intrusion into coastal aquifers can increase groundwater salinity beyond potable levels, endangering access to freshwater for millions of people. Seawater intrusion is particularly likely where water tables lie below sea level, but can also arise from groundwater pumping in some coastal aquifers with water tables above sea level. Nevertheless, no nation-wide, observation-based assessment of the scope of potential seawater intrusion exists. Here we compile and analyze ~250,000 coastal groundwater-level observations made since the year 2000 in the contiguous United States. We show that the majority of observed groundwater levels lie below sea level along more than 15% of the contiguous coastline. We conclude that landward hydraulic gradients characterize a substantial fraction of the East Coast (>18%) and Gulf Coast (>17%), and also parts of the West Coast where groundwater pumping is high. Sea level rise, coastal land subsidence, and increasing water demands will exacerbate the threat of seawater intrusion.
Acoustic spin-Chern insulator induced by synthetic spin–orbit coupling with spin conservation breaking
Authors: Deng Weiyin , Huang Xueqin , Lu Jiuyang , Peri Valerio , Li Feng , Huber Sebastian D. , Liu Zhengyou 
Published: June 2020

AbstractTopologically protected surface modes of classical waves hold the promise to enable a variety of applications ranging from robust transport of energy to reliable information processing networks. However, both the route of implementing an analogue of the quantum Hall effect as well as the quantum spin Hall effect are obstructed for acoustics by the requirement of a magnetic field, or the presence of fermionic quantum statistics, respectively. Here, we construct a two-dimensional topological acoustic crystal induced by the synthetic spin-orbit coupling, a crucial ingredient of topological insulators, with spin non-conservation. Our setup allows us to free ourselves of symmetry constraints as we rely on the concept of a non-vanishing “spin” Chern number. We experimentally characterize the emerging boundary states which we show to be gapless and helical. More importantly, we observe the spin flipping transport in an H-shaped device, demonstrating evidently the spin non-conservation of the boundary states.
An alkaloid initiates phosphodiesterase 3A–schlafen 12 dependent apoptosis without affecting the phosphodiesterase activity
Authors: Ai Youwei , He Haibing , Chen Peihao , Yan Bo , Zhang Wenbin , Ding Zhangcheng , Li Dianrong , Chen Jie , Ma Yan , Cao Yang , Zhu Jie , Li Jiaojiao , Ou Jinjie , Du Shan , Wang Xiaodong , Ma Jianzhang , Gao Shuanhu , Qi Xiangbing 
Published: June 2020

AbstractThe promotion of apoptosis in tumor cells is a popular strategy for developing anti-cancer drugs. Here, we demonstrate that the plant indole alkaloid natural product nauclefine induces apoptosis of diverse cancer cells via a PDE3A-SLFN12 dependent death pathway. Nauclefine binds PDE3A but does not inhibit the PDE3A’s phosphodiesterase activity, thus representing a previously unknown type of PDE3A modulator that can initiate apoptosis without affecting PDE3A’s canonical function. We demonstrate that PDE3A’s H840, Q975, Q1001, and F1004 residues—as well as I105 in SLFN12—are essential for nauclefine-induced PDE3A-SLFN12 interaction and cell death. Extending these molecular insights, we show in vivo that nauclefine inhibits tumor xenograft growth, doing so in a PDE3A- and SLFN12-dependent manner. Thus, beyond demonstrating potent cytotoxic effects of an alkaloid natural product, our study illustrates a potentially side-effect-reducing strategy for targeting PDE3A for anti-cancer therapeutics without affecting its phosphodiesterase activity.
In planta study of photosynthesis and photorespiration using NADPH and NADH/NAD+ fluorescent protein sensors
Authors: Lim Shey-Li , Voon Chia Pao , Guan Xiaoqian , Yang Yi , Gardeström Per , Lim Boon Leong 
Published: June 2020

AbstractThe challenge of monitoring in planta dynamic changes of NADP(H) and NAD(H) redox states at the subcellular level is considered a major obstacle in plant bioenergetics studies. Here, we introduced two circularly permuted yellow fluorescent protein sensors, iNAP and SoNar, into Arabidopsis thaliana to monitor the dynamic changes in NADPH and the NADH/NAD+ ratio. In the light, photosynthesis and photorespiration are linked to the redox states of NAD(P)H and NAD(P) pools in several subcellular compartments connected by the malate-OAA shuttles. We show that the photosynthetic increases in stromal NADPH and NADH/NAD+ ratio, but not ATP, disappear when glycine decarboxylation is inhibited. These observations highlight the complex interplay between chloroplasts and mitochondria during photosynthesis and support the suggestions that, under normal conditions, photorespiration supplies a large amount of NADH to mitochondria, exceeding its NADH-dissipating capacity, and the surplus NADH is exported from the mitochondria to the cytosol through the malate-OAA shuttle.
Cobalt-catalyzed highly enantioselective hydrogenation of α,β-unsaturated carboxylic acids
Authors: Du Xiaoyong , Xiao Ye , Huang Jia-Ming , Zhang Yao , Duan Ya-Nan , Wang Heng , Shi Chuan , Chen Gen-Qiang , Zhang Xumu 
Published: June 2020

AbstractAsymmetric hydrogenation of α,β-unsaturated acids catalyzed by noble metals has been well established, whereas, the asymmetric hydrogenation with earth-abundant-metal was rarely reported. Here, we describe a cobalt-catalyzed asymmetric hydrogenation of α,β-unsaturated carboxylic acids. By using chiral cobalt catalyst bearing electron-donating diphosphine ligand, high activity (up to 1860 TON) and excellent enantioselectivity (up to >99% ee) are observed. Furthermore, the cobalt-catalyzed asymmetric hydrogenation is successfully applied to a broad spectrum of α,β-unsaturated carboxylic acids, such as various α-aryl and α-alkyl cinnamic acid derivatives, α-oxy-functionalized α,β-unsaturated acids, α-substituted acrylic acids and heterocyclic α,β-unsaturated acids (30 examples). The synthetic utility of the protocol is highlighted by the synthesis of key intermediates for chiral drugs (6 cases). Preliminary mechanistic studies reveal that the carboxy group may be involved in the control of the reactivity and enantioselectivity through an interaction with the metal centre.
Spermine synthase and MYC cooperate to maintain colorectal cancer cell survival by repressing Bim expression
Authors: Guo Yubin , Ye Qing , Deng Pan , Cao Yanan , He Daheng , Zhou Zhaohe , Wang Chi , Zaytseva Yekaterina Y. , Schwartz Charles E. , Lee Eun Y. , Evers B. Mark , Morris Andrew J. , Liu Side , She Qing-Bai 
Published: June 2020

AbstractDysregulation of polyamine metabolism has been linked to the development of colorectal cancer (CRC), but the underlying mechanism is incompletely characterized. Here, we report that spermine synthase (SMS), a polyamine biosynthetic enzyme, is overexpressed in CRC. Targeted disruption of SMS in CRC cells results in spermidine accumulation, which inhibits FOXO3a acetylation and allows subsequent translocation to the nucleus to transcriptionally induce expression of the proapoptotic protein Bim. However, this induction is blunted by MYC-driven expression of miR-19a and miR-19b that repress Bim production. Pharmacological or genetic inhibition of MYC activity in SMS-depleted CRC cells dramatically induces Bim expression and apoptosis and causes tumor regression, but these effects are profoundly attenuated by silencing Bim. These findings uncover a key survival signal in CRC through convergent repression of Bim expression by distinct SMS- and MYC-mediated signaling pathways. Thus, combined inhibition of SMS and MYC signaling may be an effective therapy for CRC.
The receptor PTPRU is a redox sensitive pseudophosphatase
Authors: Hay Iain M. , Fearnley Gareth W. , Rios Pablo , Köhn Maja , Sharpe Hayley J. , Deane Janet E. 
Published: June 2020

AbstractThe receptor-linked protein tyrosine phosphatases (RPTPs) are key regulators of cell-cell communication through the control of cellular phosphotyrosine levels. Most human RPTPs possess an extracellular receptor domain and tandem intracellular phosphatase domains: comprising an active membrane proximal (D1) domain and an inactive distal (D2) pseudophosphatase domain. Here we demonstrate that PTPRU is unique amongst the RPTPs in possessing two pseudophosphatase domains. The PTPRU-D1 displays no detectable catalytic activity against a range of phosphorylated substrates and we show that this is due to multiple structural rearrangements that destabilise the active site pocket and block the catalytic cysteine. Upon oxidation, this cysteine forms an intramolecular disulphide bond with a vicinal “backdoor” cysteine, a process thought to reversibly inactivate related phosphatases. Importantly, despite the absence of catalytic activity, PTPRU binds substrates of related phosphatases strongly suggesting that this pseudophosphatase functions in tyrosine phosphorylation by competing with active phosphatases for the binding of substrates.
The MiDAC histone deacetylase complex is essential for embryonic development and has a unique multivalent structure
Authors: Turnbull Robert E. , Fairall Louise , Saleh Almutasem , Kelsall Emma , Morris Kyle L. , Ragan T. J. , Savva Christos G. , Chandru Aditya , Millard Christopher J. , Makarova Olga V. , Smith Corinne J. , Roseman Alan M. , Fry Andrew M. , Cowley Shaun M. , Schwabe John W. R. 
Published: June 2020

AbstractMiDAC is one of seven distinct, large multi-protein complexes that recruit class I histone deacetylases to the genome to regulate gene expression. Despite implications of involvement in cell cycle regulation and in several cancers, surprisingly little is known about the function or structure of MiDAC. Here we show that MiDAC is important for chromosome alignment during mitosis in cancer cell lines. Mice lacking the MiDAC proteins, DNTTIP1 or MIDEAS, die with identical phenotypes during late embryogenesis due to perturbations in gene expression that result in heart malformation and haematopoietic failure. This suggests that MiDAC has an essential and unique function that cannot be compensated by other HDAC complexes. Consistent with this, the cryoEM structure of MiDAC reveals a unique and distinctive mode of assembly. Four copies of HDAC1 are positioned at the periphery with outward-facing active sites suggesting that the complex may target multiple nucleosomes implying a processive deacetylase function.
Ultrafast diffusion exchange nuclear magnetic resonance
Authors: Mankinen Otto , Zhivonitko Vladimir V. , Selent Anne , Mailhiot Sarah , Komulainen Sanna , Prisle Nønne L. , Ahola Susanna , Telkki Ville-Veikko 
Published: June 2020

AbstractThe exchange of molecules between different physical or chemical environments due to diffusion or chemical transformations has a crucial role in a plethora of fundamental processes such as breathing, protein folding, chemical reactions and catalysis. Here, we introduce a method for a single-scan, ultrafast NMR analysis of molecular exchange based on the diffusion coefficient contrast. The method shortens the experiment time by one to four orders of magnitude. Consequently, it opens the way for high sensitivity quantification of important transient physical and chemical exchange processes such as in cellular metabolism. As a proof of principle, we demonstrate that the method reveals the structure of aggregates formed by surfactants relevant to aerosol research.
Histopathologic, immunophenotypic, and proteomics characteristics of low-grade phyllodes tumor and fibroadenoma: more similarities than differences
Authors: Zhang Lingxin , Yang Chen , Pfeifer John D. , Caprioli Richard M. , Judd Audra M. , Patterson Nathan H. , Reyzer Michelle L. , Norris Jeremy L. , Maluf Horacio M. 
Published: June 2020

AbstractDistinguishing low-grade phyllodes tumor from fibroadenoma is practically challenging due to their overlapping histologic features. However, the final interpretation is essential to surgeons, who base their management on the final pathology report. Patients who receive a diagnosis of fibroadenoma might not undergo any additional intervention while lumpectomy with wide margins is the standard of care for phyllodes tumor, which can have significant cosmetic consequences. We studied the clinical, immunophenotypic, and proteomics profiles of 31 histologically confirmed low-grade phyllodes tumor and 30 fibroadenomas. Matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) and immunohistochemistry for Ki-67, p53, β-catenin, and E-cadherin were performed on all cases. After the mass spectra for all 31 cases of low-grade phyllodes tumor and 30 cases of fibroadenoma were collected, an average peak value for all cases was generated. There was no significant difference in the overall mass spectra pattern in any of the peaks identified. There was also overlap in the percentage of cells staining positive for Ki-67, p53, β-catenin, and E-cadherin. The two groups of patients showed no statistically significant difference in age, tumor size, or disease-free survival. Neither group developed malignant transformation, distant metastases, or disease-related mortality. We have demonstrated low-grade phyllodes tumor and fibroadenoma to show significant overlapping clinical and proteomics features.
In vivo evaluation of porous nanohydroxyapatite/polyamide 66 struts in a goat cervical fusion model
Authors: Liang Xi , Li Feilong , Gong Xuan , Li Junchao , Yin Shijie , Li Qi , Liu Ziming , Zhao Zenghui , Tu Xiaolin , Huang Wei , Hu Ning 
Published: June 2020

AbstractThe hollow cylindrical nanohydroxyapatite/polyamide 66 strut (n-HA/PA66) has been used clinically for anterior cervical reconstruction. However, rates of occurrence of a “radiolucent gap” between the dense strut and adjacent endplates were reported. The aim of this in vivo study was to evaluate the viability and advantages of the novel porous n-HA/PA66 strut. The goat C3/4 partial discectomy and fusion model was built, and two groups of n-HA/PA66 struts were implanted into C3/4: group 1, porous n-HA/PA66 strut; and group 2, hollow cylindrical n-HA/PA66 strut filled with autogenous cancellous bone. CT evaluation was performed to assess the fusion status after 12 and 24 weeks. The cervical spines were harvested. Histomorphological analysis was performed to determine new bone formation. Biomechanical testing was performed to determine range of motion (ROM). CT confirmed the disappearance of the boundary of the porous strut and host bone, while the radiolucent gap remained clearly discernible in the dense strut group. The mean CT fusion scores of the porous group were significantly higher. Histologic evaluation showed that the porous struts promoted better osteointegration. Calcein fluorochrome labelling indicated faster bone ingrowth in the porous struts. Biomechanical tests revealed that the porous struts had significantly reduced micromotion. The porous n-HA/PA66 strut could offer interesting potential for cervical reconstruction after corpectomy.
Relationship between the characteristic traits of polycystic ovary syndrome and susceptibility genes
Authors: Hong So-hyeon , Hong Young Sun , Jeong Kyungah , Chung Hyewon , Lee Hyejin , Sung Yeon-Ah 
Published: June 2020

AbstractPolycystic ovary syndrome (PCOS) is a highly complex disorder influenced by genetic and environmental factors. Previous genome-wide association studies (GWAS) on Han Chinese, Korean, and European populations identified multiple PCOS-susceptible loci; however, only a few studies reported the association of susceptibility genes with disease phenotypic traits. This cross-sectional study aimed to investigate the association between PCOS susceptibility genes from GWAS and disease-related clinical features. A total of 1,810 reproductive-aged women were recruited, including 927 control women and 883 women with PCOS, diagnosed based on the European Society for Human Reproduction and Embryology criteria. Genomic DNA was extracted and genotyped, and a Bonferroni test was performed to determine the association between 12 independent SNPs and the clinical features of PCOS. In women with PCOS, rs11031006, nearest to FSHB, was significantly associated with free testosterone (P = 1.94 × 10−3) and luteinizing hormone (P = 1.96 × 10−3) levels. The menstruation number per year, ovarian follicular number, ovarian volume, and insulin sensitivity index were not associated with any SNP. In the control group, no SNPs were associated with any PCOS traits. Collectively, our results suggest that FSHB may play an important role in the development and progression of PCOS.
Exploratory dynamics of vocal foraging during infant-caregiver communication
Authors: Ritwika V. P. S. , Pretzer Gina M. , Mendoza Sara , Shedd Christopher , Kello Christopher T. , Gopinathan Ajay , Warlaumont Anne S. 
Published: June 2020

AbstractWe investigated the hypothesis that infants search in an acoustic space for vocalisations that elicit adult utterances and vice versa, inspired by research on animal and human foraging. Infant-worn recorders were used to collect day-long audio recordings, and infant speech-related and adult vocalisation onsets and offsets were automatically identified. We examined vocalisation-to-vocalisation steps, focusing on inter-vocalisation time intervals and distances in an acoustic space defined by mean pitch and mean amplitude, measured from the child’s perspective. Infant inter-vocalisation intervals were shorter immediately following a vocal response from an adult. Adult intervals were shorter following an infant response and adult inter-vocalisation pitch differences were smaller following the receipt of a vocal response from the infant. These findings are consistent with the hypothesis that infants and caregivers are foraging vocally for social input. Increasing infant age was associated with changes in inter-vocalisation step sizes for both infants and adults, and we found associations between response likelihood and acoustic characteristics. Future work is needed to determine the impact of different labelling methods and of automatic labelling errors on the results. The study represents a novel application of foraging theory, demonstrating how infant behaviour and infant-caregiver interaction can be characterised as foraging processes.
LoTToR: An Algorithm for Missing-Wedge Correction of the Low-Tilt Tomographic 3D Reconstruction of a Single-Molecule Structure
Authors: Zhai Xiaobo , Lei Dongsheng , Zhang Meng , Liu Jianfang , Wu Hao , Yu Yadong , Zhang Lei , Ren Gang 
Published: June 2020

AbstractA single-molecule three-dimensional (3D) structure is essential for understanding the thermal vibrations and dynamics as well as the conformational changes during the chemical reaction of macromolecules. Individual-particle electron tomography (IPET) is an approach for obtaining a snap-shot 3D structure of an individual macromolecule particle by aligning the tilt series of electron tomographic (ET) images of a targeted particle through a focused iterative 3D reconstruction method. The method can reduce the influence on the 3D reconstruction from large-scale image distortion and deformation. Due to the mechanical tilt limitation, 3D reconstruction often contains missing-wedge artifacts, presented as elongation and an anisotropic resolution. Here, we report a post-processing method to correct the missing-wedge artifact. This low-tilt tomographic reconstruction (LoTToR) method contains a model-free iteration process under a set of constraints in real and reciprocal spaces. A proof of concept is conducted by using the LoTToR on a phantom, i.e., a simulated 3D reconstruction from a low-tilt series of images, including that within a tilt range of ±15°. The method is validated by using both negative-staining (NS) and cryo-electron tomography (cryo-ET) experimental data. A significantly reduced missing-wedge artifact verifies the capability of LoTToR, suggesting a new tool to support the future study of macromolecular dynamics, fluctuation and chemical activity from the viewpoint of single-molecule 3D structure determination.