bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations
Authors: Li Yun Rose , Glessner Joseph T. , Coe Bradley P. , Li Jin , Mohebnasab Maede , Chang Xiao , Connolly John , Kao Charlly , Wei Zhi , Bradfield Jonathan , Kim Cecilia , Hou Cuiping , Khan Munir , Mentch Frank , Qiu Haijun , Bakay Marina , Cardinale Christopher , Lemma Maria , Abrams Debra , Bridglall-Jhingoor Andrew , Behr Meckenzie , Harrison Shanell , Otieno George , Thomas Alexandria , Wang Fengxiang , Chiavacci Rosetta , Wu Lawrence , Hadley Dexter , Goldmuntz Elizabeth , Elia Josephine , Maris John , Grundmeier Robert , Devoto Marcella , Keating Brendan , March Michael , Pellagrino Renata , Grant Struan F. A. , Sleiman Patrick M. A. , Li Mingyao , Eichler Evan E. , Hakonarson Hakon 
Published: January 2020

AbstractCopy number variants (CNVs) are suggested to have a widespread impact on the human genome and phenotypes. To understand the role of CNVs across human diseases, we examine the CNV genomic landscape of 100,028 unrelated individuals of European ancestry, using SNP and CGH array datasets. We observe an average CNV burden of ~650 kb, identifying a total of 11,314 deletion, 5625 duplication, and 2746 homozygous deletion CNV regions (CNVRs). In all, 13.7% are unreported, 58.6% overlap with at least one gene, and 32.8% interrupt coding exons. These CNVRs are significantly more likely to overlap OMIM genes (2.94-fold), GWAS loci (1.52-fold), and non-coding RNAs (1.44-fold), compared with random distribution (P < 1 × 10−3). We uncover CNV associations with four major disease categories, including autoimmune, cardio-metabolic, oncologic, and neurological/psychiatric diseases, and identify several drug-repurposing opportunities. Our results demonstrate robust frequency definition for large-scale rare variant association studies, identify CNVs associated with major disease categories, and illustrate the pleiotropic impact of CNVs in human disease.
STING-dependent paracriny shapes apoptotic priming of breast tumors in response to anti-mitotic treatment
Authors: Lohard Steven , Bourgeois Nathalie , Maillet Laurent , Gautier Fabien , Fétiveau Aurélie , Lasla Hamza , Nguyen Frédérique , Vuillier Céline , Dumont Alison , Moreau-Aubry Agnès , Frapin Morgane , David Laurent , Loussouarn Delphine , Kerdraon Olivier , Campone Mario , Jézéquel Pascal , Juin Philippe P. , Barillé-Nion Sophie 
Published: January 2020

AbstractA fascinating but uncharacterized action of antimitotic chemotherapy is to collectively prime cancer cells to apoptotic mitochondrial outer membrane permeabilization (MOMP), while impacting only on cycling cell subsets. Here, we show that a proapoptotic secretory phenotype is induced by activation of cGAS/STING in cancer cells that are hit by antimitotic treatment, accumulate micronuclei and maintain mitochondrial integrity despite intrinsic apoptotic pressure. Organotypic cultures of primary human breast tumors and patient-derived xenografts sensitive to paclitaxel exhibit gene expression signatures typical of type I IFN and TNFα exposure. These cytokines induced by cGAS/STING activation trigger NOXA expression in neighboring cells and render them acutely sensitive to BCL-xL inhibition. cGAS/STING-dependent apoptotic effects are required for paclitaxel response in vivo, and they are amplified by sequential, but not synchronous, administration of BH3 mimetics. Thus anti-mitotic agents propagate apoptotic priming across heterogeneously sensitive cancer cells through cytosolic DNA sensing pathway-dependent extracellular signals, exploitable by delayed MOMP targeting.
Metabolic engineering of Escherichia coli for shikimate pathway derivative production from glucose–xylose co-substrate
Authors: Fujiwara Ryosuke , Noda Shuhei , Tanaka Tsutomu , Kondo Akihiko 
Published: January 2020

AbstractGlucose and xylose are the major components of lignocellulose. Effective utilization of both sugars can improve the efficiency of bioproduction. Here, we report a method termed parallel metabolic pathway engineering (PMPE) for producing shikimate pathway derivatives from glucose–xylose co-substrate. In this method, we seek to use glucose mainly for target chemical production, and xylose for supplying essential metabolites for cell growth. Glycolysis and the pentose phosphate pathway are completely separated from the tricarboxylic acid (TCA) cycle. To recover cell growth, we introduce a xylose catabolic pathway that directly flows into the TCA cycle. As a result, we can produce 4.09 g L−1cis,cis-muconic acid using the PMPE Escherichia coli strain with high yield (0.31 g g−1 of glucose) and produce l-tyrosine with 64% of the theoretical yield. The PMPE strategy can contribute to the development of clean processes for producing various valuable chemicals from lignocellulosic resources.
Spin pumping during the antiferromagnetic–ferromagnetic phase transition of iron–rhodium
Authors: Wang Yuyan , Decker Martin M. , Meier Thomas N. G. , Chen Xianzhe , Song Cheng , Grünbaum Tobias , Zhao Weisheng , Zhang Junying , Chen Lin , Back Christian H. 
Published: January 2020

AbstractFeRh attracts intensive interest in antiferromagnetic (AFM) spintronics due to its first-order phase transition between the AFM and ferromagnetic (FM) phase, which is unique for exploring spin dynamics in coexisting phases. Here, we report lateral spin pumping by which angular momentum is transferred from FM domains into the AFM matrix during the phase transition of ultrathin FeRh films. In addition, FeRh is verified to be both an efficient spin generator and an efficient spin sink, by electrically probing vertical spin pumping from FM-FeRh into Pt and from Py into FeRh, respectively. A dramatic enhancement of damping related to AFM-FeRh is observed during the phase transition, which we prove to be dominated by lateral spin pumping across the FM/AFM interface. The discovery of lateral spin pumping provides insight into the spin dynamics of magnetic thin films with mixed-phases, and the significantly modulated damping advances its potential applications, such as ultrafast spintronics.
Bright ligand-activatable fluorescent protein for high-quality multicolor live-cell super-resolution microscopy
Authors: Kwon Jiwoong , Park Jong-Seok , Kang Minsu , Choi Soobin , Park Jumi , Kim Gyeong Tae , Lee Changwook , Cha Sangwon , Rhee Hyun-Woo , Shim Sang-Hee 
Published: January 2020

AbstractWe introduce UnaG as a green-to-dark photoswitching fluorescent protein capable of high-quality super-resolution imaging with photon numbers equivalent to the brightest photoswitchable red protein. UnaG only fluoresces upon binding of a fluorogenic metabolite, bilirubin, enabling UV-free reversible photoswitching with easily controllable kinetics and low background under Epi illumination. The on- and off-switching rates are controlled by the concentration of the ligand and the excitation light intensity, respectively, where the dissolved oxygen also promotes the off-switching. The photo-oxidation reaction mechanism of bilirubin in UnaG suggests that the lack of ligand-protein covalent bond allows the oxidized ligand to detach from the protein, emptying the binding cavity for rebinding to a fresh ligand molecule. We demonstrate super-resolution single-molecule localization imaging of various subcellular structures genetically encoded with UnaG, which enables facile labeling and simultaneous multicolor imaging of live cells. UnaG has the promise of becoming a default protein for high-performance super-resolution imaging.
Phase separation of TPX2 enhances and spatially coordinates microtubule nucleation
Authors: King Matthew R. , Petry Sabine 
Published: January 2020

AbstractPhase separation of substrates and effectors is proposed to enhance biological reaction rates and efficiency. Targeting protein for Xklp2 (TPX2) is an effector of branching microtubule nucleation in spindles and functions with the substrate tubulin by an unknown mechanism. Here we show that TPX2 phase separates into a co-condensate with tubulin, which mediates microtubule nucleation in vitro and in isolated cytosol. TPX2-tubulin co-condensation preferentially occurs on pre-existing microtubules, the site of branching microtubule nucleation, at the endogenous and physiologically relevant concentration of TPX2. Truncation and chimera versions of TPX2 suggest that TPX2-tubulin co-condensation enhances the efficiency of TPX2-mediated branching microtubule nucleation. Finally, the known inhibitor of TPX2, the importin-α/β heterodimer, regulates TPX2 condensation in vitro and, consequently, branching microtubule nucleation activity in isolated cytosol. Our study demonstrates how regulated phase separation can simultaneously enhance reaction efficiency and spatially coordinate microtubule nucleation, which may facilitate rapid and accurate spindle formation.
Gold endowments of porphyry deposits controlled by precipitation efficiency
Authors: Chiaradia Massimo 
Published: January 2020

AbstractPorphyry deposits are natural suppliers of most copper and significant gold to our society. Whereas the Cu-richest (Au-poor) porphyries are related to Andean-type subduction and typical calc-alkaline magmatism, the Au-richest porphyries are associated with high-K calc-alkaline to alkaline magmatism in late to post-subduction or post-collision and extensional settings, and subordinately with calc-alkaline magmatism. The reasons behind these associations and the large variations in metal endowments of porphyry Cu–Au deposits remain obscure. Here, I show that porphyry Cu–Au deposits define two distinct trends in Au vs. Cu tonnage plots (Cu-rich and Au-rich). Metal endowments for both trends grow larger the longer the mineralization process. However, Au is precipitated at much higher rates in Au-rich than in Cu-rich porphyry deposits. Using Monte Carlo simulations of petrologic processes, I show that whereas Cu-rich porphyries require large amounts of magma and water to be formed, Au-rich porphyries are the result of a better efficiency of Au precipitation.
A mosquito salivary protein promotes flavivirus transmission by activation of autophagy
Authors: Sun Peng , Nie Kaixiao , Zhu Yibin , Liu Yang , Wu Pa , Liu Ziwen , Du Senyan , Fan Huahao , Chen Chun-Hong , Zhang Renli , Wang Penghua , Cheng Gong 
Published: January 2020

AbstractTransmission from an infected mosquito to a host is an essential process in the life cycle of mosquito-borne flaviviruses. Numerous studies have demonstrated that mosquito saliva facilitates viral transmission. Here we find that a saliva-specific protein, named Aedes aegypti venom allergen-1 (AaVA-1), promotes dengue and Zika virus transmission by activating autophagy in host immune cells of the monocyte lineage. The AG6 mice (ifnar1–/–ifngr1–/–) bitten by the virus-infected AaVA-1-deficient mosquitoes present a lower viremia and prolonged survival. AaVA-1 intracellularly interacts with a dominant negative binder of Beclin-1, known as leucine-rich pentatricopeptide repeat-containing protein (LRPPRC), and releases Beclin-1 from LRPPRC-mediated sequestration, thereby enabling the initialization of downstream autophagic signaling. A deficiency in Beclin-1 reduces viral infection in mice and abolishes AaVA-1-mediated enhancement of ZIKV transmission by mosquitoes. Our study provides a mechanistic insight into saliva-aided viral transmission and could offer a potential prophylactic target for reducing flavivirus transmission.
Cysteine-encoded chirality evolution in plasmonic rhombic dodecahedral gold nanoparticles
Authors: Lee Hye-Eun , Kim Ryeong Myeong , Ahn Hyo-Yong , Lee Yoon Young , Byun Gi Hyun , Im Sang Won , Mun Jungho , Rho Junsuk , Nam Ki Tae 
Published: January 2020

AbstractChiral plasmonic nanostructures have opened up unprecedented opportunities in optical applications. We present chirality evolution in nanoparticles focusing on the crystallographic aspects and elucidate key parameters for chiral structure formation. From a detailed understanding of chirality formation, we achieved a morphology (432 Helicoid IV) of three-dimensionally controlled chiral plasmonic nanoparticles based on the rhombic dodecahedral shape. The role of the synthesis parameters, seed, cysteine, cetyltrimethylammonium bromide and ascorbic acid on chiral formation are studied, and based on this understanding, the systematic control of the chiral structure is presented. The relation between the modulated chiral structure factors and optical response is further elucidated by electromagnetic simulation. Importantly, a new optical response is achieved by assembling chiral nanoparticles into a film. This comprehensive study of chiral nanoparticles will provide valuable insight for the further development of diverse chiral plasmonic nanostructures with fascinating properties.
Sensitive detection of a bacterial pathogen using allosteric probe-initiated catalysis and CRISPR-Cas13a amplification reaction
Authors: Shen Jinjin , Zhou Xiaoming , Shan Yuanyue , Yue Huahua , Huang Ru , Hu Jiaming , Xing Da 
Published: January 2020

AbstractThe ability to detect low numbers of microbial cells in food and clinical samples is highly valuable but remains a challenge. Here we present a detection system (called ‘APC-Cas’) that can detect very low numbers of a bacterial pathogen without isolation, using a three-stage amplification to generate powerful fluorescence signals. APC-Cas involves a combination of nucleic acid-based allosteric probes and CRISPR-Cas13a components. It can selectively and sensitively quantify Salmonella Enteritidis cells (from 1 to 105 CFU) in various types of samples such as milk, showing similar or higher sensitivity and accuracy compared with conventional real-time PCR. Furthermore, APC-Cas can identify low numbers of S. Enteritidis cells in mouse serum, distinguishing mice with early- and late-stage infection from uninfected mice. Our method may have potential clinical applications for early diagnosis of pathogens.
Efficient electrochemical production of glucaric acid and H2 via glucose electrolysis
Authors: Liu Wu-Jun , Xu Zhuoran , Zhao Dongting , Pan Xiao-Qiang , Li Hong-Chao , Hu Xiao , Fan Zhi-Yong , Wang Wei-Kang , Zhao Guo-Hua , Jin Song , Huber George W. , Yu Han-Qing 
Published: January 2020

AbstractGlucose electrolysis offers a prospect of value-added glucaric acid synthesis and energy-saving hydrogen production from the biomass-based platform molecules. Here we report that nanostructured NiFe oxide (NiFeOx) and nitride (NiFeNx) catalysts, synthesized from NiFe layered double hydroxide nanosheet arrays on three-dimensional Ni foams, demonstrate a high activity and selectivity towards anodic glucose oxidation. The electrolytic cell assembled with these two catalysts can deliver 100 mA cm−2 at 1.39 V. A faradaic efficiency of 87% and glucaric acid yield of 83% are obtained from the glucose electrolysis, which takes place via a guluronic acid pathway evidenced by in-situ infrared spectroscopy. A rigorous process model combined with a techno-economic analysis shows that the electrochemical reduction of glucose produces glucaric acid at a 54% lower cost than the current chemical approach. This work suggests that glucose electrolysis is an energy-saving and cost-effective approach for H2 production and biomass valorization.
A bioinspired analogous nerve towards artificial intelligence
Authors: Liao Xinqin , Song Weitao , Zhang Xiangyu , Yan Chaoqun , Li Tianliang , Ren Hongliang , Liu Cunzhi , Wang Yongtian , Zheng Yuanjin 
Published: January 2020

AbstractA bionic artificial device commonly integrates various distributed functional units to mimic the functions of biological sensory neural system, bringing intricate interconnections, complicated structure, and interference in signal transmission. Here we show an all-in-one bionic artificial nerve based on a separate electrical double-layers structure that integrates the functions of perception, recognition, and transmission. The bionic artificial nerve features flexibility, rapid response (<21 ms), high robustness, excellent durability (>10,000 tests), personalized cutability, and no energy consumption when no mechanical stimulation is being applied. The response signals are highly regionally differentiated for the mechanical stimulations, which enables the bionic artificial nerve to mimic the spatiotemporally dynamic logic of a biological neural network. Multifunctional touch interactions demonstrate the enormous potential of the bionic artificial nerve for human-machine hybrid perceptual enhancement. By incorporating the spatiotemporal resolution function and algorithmic analysis, we hope that bionic artificial nerves will promote further development of sophisticated neuroprosthetics and intelligent robotics.
Global optimization of quantum dynamics with AlphaZero deep exploration
Authors: Dalgaard Mogens , Motzoi Felix , Sørensen Jens Jakob , Sherson Jacob 
Published: January 2020

AbstractWhile a large number of algorithms for optimizing quantum dynamics for different objectives have been developed, a common limitation is the reliance on good initial guesses, being either random or based on heuristics and intuitions. Here we implement a tabula rasa deep quantum exploration version of the Deepmind AlphaZero algorithm for systematically averting this limitation. AlphaZero employs a deep neural network in conjunction with deep lookahead in a guided tree search, which allows for predictive hidden-variable approximation of the quantum parameter landscape. To emphasize transferability, we apply and benchmark the algorithm on three classes of control problems using only a single common set of algorithmic hyperparameters. AlphaZero achieves substantial improvements in both the quality and quantity of good solution clusters compared to earlier methods. It is able to spontaneously learn unexpected hidden structure and global symmetry in the solutions, going beyond even human heuristics.
Deep learning, computer-aided radiography reading for tuberculosis: a diagnostic accuracy study from a tertiary hospital in India
Authors: Nash Madlen , Kadavigere Rajagopal , Andrade Jasbon , Sukumar Cynthia Amrutha , Chawla Kiran , Shenoy Vishnu Prasad , Pande Tripti , Huddart Sophie , Pai Madhukar , Saravu Kavitha 
Published: January 2020

AbstractIn general, chest radiographs (CXR) have high sensitivity and moderate specificity for active pulmonary tuberculosis (PTB) screening when interpreted by human readers. However, they are challenging to scale due to hardware costs and the dearth of professionals available to interpret CXR in low-resource, high PTB burden settings. Recently, several computer-aided detection (CAD) programs have been developed to facilitate automated CXR interpretation. We conducted a retrospective case-control study to assess the diagnostic accuracy of a CAD software (qXR, Qure.ai, Mumbai, India) using microbiologically-confirmed PTB as the reference standard. To assess overall accuracy of qXR, receiver operating characteristic (ROC) analysis was used to determine the area under the curve (AUC), along with 95% confidence intervals (CI). Kappa coefficients, and associated 95% CI, were used to investigate inter-rater reliability of the radiologists for detection of specific chest abnormalities. In total, 317 cases and 612 controls were included in the analysis. The AUC for qXR for the detection of microbiologically-confirmed PTB was 0.81 (95% CI: 0.78, 0.84). Using the threshold that maximized sensitivity and specificity of qXR simultaneously, the software achieved a sensitivity and specificity of 71% (95% CI: 66%, 76%) and 80% (95% CI: 77%, 83%), respectively. The sensitivity and specificity of radiologists for the detection of microbiologically-confirmed PTB was 56% (95% CI: 50%, 62%) and 80% (95% CI: 77%, 83%), respectively. For detection of key PTB-related abnormalities ‘pleural effusion’ and ‘cavity’, qXR achieved an AUC of 0.94 (95% CI: 0.92, 0.96) and 0.84 (95% CI: 0.82, 0.87), respectively. For the other abnormalities, the AUC ranged from 0.75 (95% CI: 0.70, 0.80) to 0.94 (95% CI: 0.91, 0.96). The controls had a high prevalence of other lung diseases which can cause radiological manifestations similar to PTB (e.g., 26% had pneumonia, 15% had lung malignancy, etc.). In a tertiary hospital in India, qXR demonstrated moderate sensitivity and specificity for the detection of PTB. There is likely a larger role for CAD software as a triage test for PTB at the primary care level in settings where access to radiologists in limited. Larger prospective studies that can better assess heterogeneity in important subgroups are needed.
Troponin destabilization impairs sarcomere-cytoskeleton interactions in iPSC-derived cardiomyocytes from dilated cardiomyopathy patients
Authors: Dai Yuanyuan , Amenov Asset , Ignatyeva Nadezda , Koschinski Andreas , Xu Hang , Soong Poh Loong , Tiburcy Malte , Linke Wolfgang A. , Zaccolo Manuela , Hasenfuss Gerd , Zimmermann Wolfram-Hubertus , Ebert Antje 
Published: January 2020

AbstractThe sarcomeric troponin-tropomyosin complex is a critical mediator of excitation-contraction coupling, sarcomeric stability and force generation. We previously reported that induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from patients with a dilated cardiomyopathy (DCM) mutation, troponin T (TnT)-R173W, display sarcomere protein misalignment and impaired contractility. Yet it is not known how TnT mutation causes dysfunction of sarcomere microdomains and how these events contribute to misalignment of sarcomeric proteins in presence of DCM TnT-R173W. Using a human iPSC-CM model combined with CRISPR/Cas9-engineered isogenic controls, we uncovered that TnT-R173W destabilizes molecular interactions of troponin with tropomyosin, and limits binding of PKA to local sarcomere microdomains. This attenuates troponin phosphorylation and dysregulates local sarcomeric microdomains in DCM iPSC-CMs. Disrupted microdomain signaling impairs MYH7-mediated, AMPK-dependent sarcomere-cytoskeleton filament interactions and plasma membrane attachment. Small molecule-based activation of AMPK can restore TnT microdomain interactions, and partially recovers sarcomere protein misalignment as well as impaired contractility in DCM TnT-R173W iPSC-CMs. Our findings suggest a novel therapeutic direction targeting sarcomere- cytoskeleton interactions to induce sarcomere re-organization and contractile recovery in DCM.
The N-terminal Acetylation of α-Synuclein Changes the Affinity for Lipid Membranes but not the Structural Properties of the Bound State
Authors: Runfola Matteo , De Simone Alfonso , Vendruscolo Michele , Dobson Christopher M. , Fusco Giuliana 
Published: January 2020

AbstractThe aggregation of α-synuclein (αS), a protein abundant at presynaptic terminals, is associated with a range of highly debilitating neurodegenerative conditions, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Emerging evidence indicates that the interaction of αS with lipid membranes defines both its physiological function and pathological effects. The characterisation of the modes of membrane binding by αS is therefore crucial to clarify the balance between normal and aberrant behaviour of this protein. Here we used solid-state nuclear magnetic resonance (ssNMR) spectroscopy to probe the nature of the N-terminally acetylated form of αS (NTAc-αS) bound to synaptic-like lipid vesicles. This post-translational modification is prevalent for the physiological form of αS and modulates the binding to lipid bilayers. By probing the structure, dynamics and membrane topology of NTAc-αS, we found that N-terminal acetylation does not alter significantly the conformational and topological properties of the membrane-bound state of αS, despite increasing its propensity for binding. Taken together, our data and previous characterisations of the cytosolic state of NTAc-αS clarify that the role of the N-terminal acetylation is to regulate the binding affinity of αS for synaptic vesicles without altering the structural properties of the bound state.