bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance
Authors: Zatreanu Diana , Robinson Helen M. R. , Alkhatib Omar , Boursier Marie , Finch Harry , Geo Lerin , Grande Diego , Grinkevich Vera , Heald Robert A. , Langdon Sophie , Majithiya Jayesh , McWhirter Claire , Martin Niall M. B. , Moore Shaun , Neves Joana , Rajendra Eeson , Ranzani Marco , Schaedler Theresia , Stockley Martin , Wiggins Kimberley , Brough Rachel , Sridhar Sandhya , Gulati Aditi , Shao Nan , Badder Luned M. , Novo Daniela , Knight Eleanor G. , Marlow Rebecca , Haider Syed , Callen Elsa , Hewitt Graeme , Schimmel Joost , Prevo Remko , Alli Christina , Ferdinand Amanda , Bell Cameron , Blencowe Peter , Bot Chris , Calder Mathew , Charles Mark , Curry Jayne , Ekwuru Tennyson , Ewings Katherine , Krajewski Wojciech , MacDonald Ellen , McCarron Hollie , Pang Leon , Pedder Chris , Rigoreau Laurent , Swarbrick Martin , Wheatley Ed , Willis Simon , Wong Ai Ching , Nussenzweig Andre , Tijsterman Marcel , Tutt Andrew , Boulton Simon J. , Higgins Geoff S. , Pettitt Stephen J. , Smith Graeme C. M. , Lord Christopher J. 
Published: June 2021

AbstractTo identify approaches to target DNA repair vulnerabilities in cancer, we discovered nanomolar potent, selective, low molecular weight (MW), allosteric inhibitors of the polymerase function of DNA polymerase Polθ, including ART558. ART558 inhibits the major Polθ-mediated DNA repair process, Theta-Mediated End Joining, without targeting Non-Homologous End Joining. In addition, ART558 elicits DNA damage and synthetic lethality in BRCA1- or BRCA2-mutant tumour cells and enhances the effects of a PARP inhibitor. Genetic perturbation screening revealed that defects in the 53BP1/Shieldin complex, which cause PARP inhibitor resistance, result in in vitro and in vivo sensitivity to small molecule Polθ polymerase inhibitors. Mechanistically, ART558 increases biomarkers of single-stranded DNA and synthetic lethality in 53BP1-defective cells whilst the inhibition of DNA nucleases that promote end-resection reversed these effects, implicating these in the synthetic lethal mechanism-of-action. Taken together, these observations describe a drug class that elicits BRCA-gene synthetic lethality and PARP inhibitor synergy, as well as targeting a biomarker-defined mechanism of PARPi-resistance.
CRISPR-Associated Primase-Polymerases are implicated in prokaryotic CRISPR-Cas adaptation
Authors: Zabrady Katerina , Zabrady Matej , Kolesar Peter , Li Arthur W. H. , Doherty Aidan J. 
Published: June 2021

AbstractCRISPR-Cas pathways provide prokaryotes with acquired “immunity” against foreign genetic elements, including phages and plasmids. Although many of the proteins associated with CRISPR-Cas mechanisms are characterized, some requisite enzymes remain elusive. Genetic studies have implicated host DNA polymerases in some CRISPR-Cas systems but CRISPR-specific replicases have not yet been discovered. We have identified and characterised a family of CRISPR-Associated Primase-Polymerases (CAPPs) in a range of prokaryotes that are operonically associated with Cas1 and Cas2. CAPPs belong to the Primase-Polymerase (Prim-Pol) superfamily of replicases that operate in various DNA repair and replication pathways that maintain genome stability. Here, we characterise the DNA synthesis activities of bacterial CAPP homologues from Type IIIA and IIIB CRISPR-Cas systems and establish that they possess a range of replicase activities including DNA priming, polymerisation and strand-displacement. We demonstrate that CAPPs operonically-associated partners, Cas1 and Cas2, form a complex that possesses spacer integration activity. We show that CAPPs physically associate with the Cas proteins to form bespoke CRISPR-Cas complexes. Finally, we propose how CAPPs activities, in conjunction with their partners, may function to undertake key roles in CRISPR-Cas adaptation.
BNT162b2 vaccine uptake and effectiveness in UK healthcare workers – a single centre cohort study
Authors: Azamgarhi Tariq , Hodgkinson Michelle , Shah Ashik , Skinner John A. , Hauptmannova Iva , Briggs Tim W. R. , Warren Simon 
Published: June 2021

AbstractIn this single centre cohort study we assessed BNT162B2 vaccine uptake and effectiveness among UK healthcare workers (HCWs) during a time of high community COVID-19 prevalence. Early uptake among HCWs was 62.3% (1409/2260), however there were significant differences in uptake between age groups, ethnic origins, and job roles. Uptake increased to 72.9% after a vaccine hesitancy working group implemented specific measures. In the 42 days after vaccination, 49 new cases of COVID-19 were identified, of which 7 (14.3%) occurred in HCWs who were beyond 10 days of vaccination. Kaplan–Meier curves for partially vaccinated and unvaccinated groups were congruent until day 14 and continued to diverge up to 42 days. Cox regression analysis showed a 70.0% (95%CI 6.0–91.0; p=0.04) risk reduction for COVID-19 infection in partially vaccinated HCWs. Here we report early vaccination rates among HCWs are generally high although uptake is lower in certain groups. It is possible to improve vaccine uptake and efforts should focus on this, however, significant resource is required. The BNT162B2 vaccine is effective from 14 days post-vaccination in a frontline clinical setting and protection continues beyond 21 days post 1st dose without a 2nd dose, being given.
C(sp3)−C(sp3) bond formation via nickel-catalyzed deoxygenative homo-coupling of aldehydes/ketones mediated by hydrazine
Authors: Cao Dawei , Li Chen-Chen , Zeng Huiying , Peng Yong , Li Chao-Jun 
Published: June 2021

AbstractAldehydes and ketones are widely found in biomass resources and play important roles in organic synthesis. However, the direct deoxygenative coupling of aldehydes or ketones to construct C(sp3)−C(sp3) bond remains a scientific challenge. Here we report a nickel−catalyzed reductive homo-coupling of moisture- and air-stable hydrazones generated in-situ from naturally abundant aldehydes and ketones to construct challenging C(sp3)−C(sp3) bond. This transformation has great functional group compatibility and can suit a broad substrate scope with innocuous H2O, N2 and H2 as the by-products. Furthermore, the application in several biological molecules and the transformation of PEEK model demonstrate the generality, practicability, and applicability of this novel methodology.
MolDiscovery: learning mass spectrometry fragmentation of small molecules
Authors: Cao Liu , Guler Mustafa , Tagirdzhanov Azat , Lee Yi-Yuan , Gurevich Alexey , Mohimani Hosein 
Published: June 2021

AbstractIdentification of small molecules is a critical task in various areas of life science. Recent advances in mass spectrometry have enabled the collection of tandem mass spectra of small molecules from hundreds of thousands of environments. To identify which molecules are present in a sample, one can search mass spectra collected from the sample against millions of molecular structures in small molecule databases. The existing approaches are based on chemistry domain knowledge, and they fail to explain many of the peaks in mass spectra of small molecules. Here, we present molDiscovery, a mass spectral database search method that improves both efficiency and accuracy of small molecule identification by learning a probabilistic model to match small molecules with their mass spectra. A search of over 8 million spectra from the Global Natural Product Social molecular networking infrastructure shows that molDiscovery correctly identify six times more unique small molecules than previous methods.
Efficient precise in vivo base editing in adult dystrophic mice
Authors: Xu Li , Zhang Chen , Li Haiwen , Wang Peipei , Gao Yandi , Mokadam Nahush A. , Ma Jianjie , Arnold W. David , Han Renzhi 
Published: June 2021

AbstractRecent advances in base editing have created an exciting opportunity to precisely correct disease-causing mutations. However, the large size of base editors and their inherited off-target activities pose challenges for in vivo base editing. Moreover, the requirement of a protospacer adjacent motif (PAM) nearby the mutation site further limits the targeting feasibility. Here we modify the NG-targeting adenine base editor (iABE-NGA) to overcome these challenges and demonstrate the high efficiency to precisely edit a Duchenne muscular dystrophy (DMD) mutation in adult mice. Systemic delivery of AAV9-iABE-NGA results in dystrophin restoration and functional improvement. At 10 months after AAV9-iABE-NGA treatment, a near complete rescue of dystrophin is measured in mdx4cv mouse hearts with up to 15% rescue in skeletal muscle fibers. The off-target activities remains low and no obvious toxicity is detected. This study highlights the promise of permanent base editing using iABE-NGA for the treatment of monogenic diseases.
Model-based prediction of spatial gene expression via generative linear mapping
Authors: Okochi Yasushi , Sakaguchi Shunta , Nakae Ken , Kondo Takefumi , Naoki Honda 
Published: June 2021

AbstractDecoding spatial transcriptomes from single-cell RNA sequencing (scRNA-seq) data has become a fundamental technique for understanding multicellular systems; however, existing computational methods lack both accuracy and biological interpretability due to their model-free frameworks. Here, we introduce Perler, a model-based method to integrate scRNA-seq data with reference in situ hybridization (ISH) data. To calibrate differences between these datasets, we develop a biologically interpretable model that uses generative linear mapping based on a Gaussian mixture model using the Expectation–Maximization algorithm. Perler accurately predicts the spatial gene expression of Drosophila embryos, zebrafish embryos, mammalian liver, and mouse visual cortex from scRNA-seq data. Furthermore, the reconstructed transcriptomes do not over-fit the ISH data and preserved the timing information of the scRNA-seq data. These results demonstrate the generalizability of Perler for dataset integration, thereby providing a biologically interpretable framework for accurate reconstruction of spatial transcriptomes in any multicellular system.
Triboelectrification induced self-powered microbial disinfection using nanowire-enhanced localized electric field
Authors: Huo Zheng-Yang , Kim Young-Jun , Suh In-Yong , Lee Dong-Min , Lee Jeong Hwan , Du Ye , Wang Si , Yoon Hong-Joon , Kim Sang-Woo 
Published: June 2021

AbstractAir-transmitted pathogens may cause severe epidemics showing huge threats to public health. Microbial inactivation in the air is essential, whereas the feasibility of existing air disinfection technologies meets challenges including only achieving physical separation but no inactivation, obvious pressure drops, and energy intensiveness. Here we report a rapid disinfection method toward air-transmitted bacteria and viruses using the nanowire-enhanced localized electric field to damage the outer structures of microbes. This air disinfection system is driven by a triboelectric nanogenerator that converts mechanical vibration to electricity effectively and achieves self-powered. Assisted by a rational design for the accelerated charging and trapping of microbes, this air disinfection system promotes microbial transport and achieves high performance: >99.99% microbial inactivation within 0.025 s in a fast airflow (2 m/s) while only causing low pressure drops (<24 Pa). This rapid, self-powered air disinfection method may fill the urgent need for air-transmitted microbial inactivation to protect public health.
Efficient ethylene purification by a robust ethane-trapping porous organic cage
Authors: Su Kongzhao , Wang Wenjing , Du Shunfu , Ji Chunqing , Yuan Daqiang 
Published: June 2021

AbstractThe removal of ethane (C2H6) from its analogous ethylene (C2H4) is of paramount importance in the petrochemical industry, but highly challenging due to their similar physicochemical properties. The use of emerging porous organic cage (POC) materials for C2H6/C2H4 separation is still in its infancy. Here, we report the benchmark example of a truncated octahedral calix[4]resorcinarene-based POC adsorbent (CPOC-301), preferring to adsorb C2H6 than C2H4, and thus can be used as a robust absorbent to directly separate high-purity C2H4 from the C2H6/C2H4 mixture. Molecular modelling studies suggest the exceptional C2H6 selectivity is due to the suitable resorcin[4]arene cavities in CPOC-301, which form more multiple C–H···π hydrogen bonds with C2H6 than with C2H4 guests. This work provides a fresh avenue to utilize POC materials for highly selective separation of industrially important hydrocarbons.
Mechanistic analysis of multiple processes controlling solar-driven H2O2 synthesis using engineered polymeric carbon nitride
Authors: Zhao Yubao , Zhang Peng , Yang Zhenchun , Li Lina , Gao Jingyu , Chen Sheng , Xie Tengfeng , Diao Caozheng , Xi Shibo , Xiao Beibei , Hu Chun , Choi Wonyong 
Published: June 2021

AbstractSolar-driven hydrogen peroxide (H2O2) production presents unique merits of sustainability and environmental friendliness. Herein, efficient solar-driven H2O2production through dioxygen reduction is achieved by employing polymeric carbon nitride framework with sodium cyanaminate moiety, affording a H2O2production rate of 18.7 μmol h−1mg−1and an apparent quantum yield of 27.6% at 380 nm. The overall photocatalytic transformation process is systematically analyzed, and some previously unknown structural features and interactions are substantiated via experimental and theoretical methods. The structural features of cyanamino group and pyridinic nitrogen-coordinated soidum in the framework promote photon absorption, alter the energy landscape of the framework and improve charge separation efficiency, enhance surface adsorption of dioxygen, and create selective 2e−oxygen reduction reaction surface-active sites. Particularly, an electronic coupling interaction between O2and surface, which boosts the population and prolongs the lifetime of the active shallow-trapped electrons, is experimentally substantiated.
Bicyclo[2.2.0]hexene derivatives as a proaromatic platform for group transfer and chemical sensing
Authors: Wu Bin , Wang Jianing , Liu Xingchen , Zhu Rong 
Published: June 2021

AbstractHere we report the design, preparation, synthetic utility, and sensing application of a class of proaromatic structures, namely bicyclo[2.2.0]hexene (BCH) derivatives. Building on a valence isomerism concept, they feature modular and easy synthesis as well as high thermal stability, and can be oxidatively activated under mild conditions. New alkyl transfer reactions using BCHs as a radical donor have been developed to showcase the utility of their proaromaticity. Moreover, the redox-triggered valence isomerization of a quinoline-derived BCH led to colorimetric and fluorescent responses toward vapors of electrophilic reagents in solution and solid phase, respectively. This optical response was shown to involve a 1,3-cyclohexadiene structure that possesses an intramolecular charge transfer excited state with interesting aggregation induced emission (AIE) character. Thus, the potential of BCHs has been demonstrated as a versatile platform for the development of new reagents and functional materials.
Halide perovskite memristors as flexible and reconfigurable physical unclonable functions
Authors: John Rohit Abraham , Shah Nimesh , Vishwanath Sujaya Kumar , Ng Si En , Febriansyah Benny , Jagadeeswararao Metikoti , Chang Chip-Hong , Basu Arindam , Mathews Nripan 
Published: June 2021

AbstractPhysical Unclonable Functions (PUFs) address the inherent limitations of conventional hardware security solutions in edge-computing devices. Despite impressive demonstrations with silicon circuits and crossbars of oxide memristors, realizing efficient roots of trust for resource-constrained hardware remains a significant challenge. Hybrid organic electronic materials with a rich reservoir of exotic switching physics offer an attractive, inexpensive alternative to design efficient cryptographic hardware, but have not been investigated till date. Here, we report a breakthrough security primitive exploiting the switching physics of one dimensional halide perovskite memristors as excellent sources of entropy for secure key generation and device authentication. Measurements of a prototypical 1 kb propyl pyridinium lead iodide (PrPyr[PbI3]) weak memristor PUF with a differential write-back strategy reveals near ideal uniformity, uniqueness and reliability without additional area and power overheads. Cycle-to-cycle write variability enables reconfigurability, while in-memory computing empowers a strong recurrent PUF construction to thwart machine learning attacks.
Neighborhood-level disparities and subway utilization during the COVID-19 pandemic in New York City
Authors: Carrión Daniel , Colicino Elena , Pedretti Nicolo Foppa , Arfer Kodi B. , Rush Johnathan , DeFelice Nicholas , Just Allan C. 
Published: June 2021

AbstractThe COVID-19 pandemic has yielded disproportionate impacts on communities of color in New York City (NYC). Researchers have noted that social disadvantage may result in limited capacity to socially distance, and consequent disparities. We investigate the association between neighborhood social disadvantage and the ability to socially distance, infections, and mortality in Spring 2020. We combine Census Bureau and NYC open data with SARS-CoV-2 testing data using supervised dimensionality-reduction with Bayesian Weighted Quantile Sums regression. The result is a ZIP code-level index with weighted social factors associated with infection risk. We find a positive association between neighborhood social disadvantage and infections, adjusting for the number of tests administered. Neighborhood disadvantage is also associated with a proxy of the capacity to socially isolate, NYC subway usage data. Finally, our index is associated with COVID-19-related mortality.
Nonlinearity-induced nanoparticle circumgyration at sub-diffraction scale
Authors: Qin Yaqiang , Zhou Lei-Ming , Huang Lu , Jin Yunfeng , Shi Hao , Shi Shali , Guo Honglian , Xiao Liantuan , Yang Yuanjie , Qiu Cheng-Wei , Jiang Yuqiang 
Published: June 2021

AbstractThe ability of light beams to rotate nano-objects has important applications in optical micromachines and biotechnology. However, due to the diffraction limit, it is challenging to rotate nanoparticles at subwavelength scale. Here, we propose a method to obtain controlled fast orbital rotation (i.e., circumgyration) at deep subwavelength scale, based on the nonlinear optical effect rather than sub-diffraction focusing. We experimentally demonstrate rotation of metallic nanoparticles with orbital radius of 71 nm, to our knowledge, the smallest orbital radius obtained by optical trapping thus far. The circumgyration frequency of particles in water can be more than 1 kHz. In addition, we use a femtosecond pulsed Gaussian beam rather than vortex beams in the experiment. Our study provides paradigms for nanoparticle manipulation beyond the diffraction limit, which will not only push toward possible applications in optically driven nanomachines, but also spur more fascinating research in nano-rheology, micro-fluid mechanics and biological applications at the nanoscale.
Single-cell RNA-seq reveals fibroblast heterogeneity and increased mesenchymal fibroblasts in human fibrotic skin diseases
Authors: Deng Cheng-Cheng , Hu Yong-Fei , Zhu Ding-Heng , Cheng Qing , Gu Jing-Jing , Feng Qing-Lan , Zhang Li-Xue , Xu Ying-Ping , Wang Dong , Rong Zhili , Yang Bin 
Published: June 2021

AbstractFibrotic skin disease represents a major global healthcare burden, characterized by fibroblast hyperproliferation and excessive accumulation of extracellular matrix. Fibroblasts are found to be heterogeneous in multiple fibrotic diseases, but fibroblast heterogeneity in fibrotic skin diseases is not well characterized. In this study, we explore fibroblast heterogeneity in keloid, a paradigm of fibrotic skin diseases, by using single-cell RNA-seq. Our results indicate that keloid fibroblasts can be divided into 4 subpopulations: secretory-papillary, secretory-reticular, mesenchymal and pro-inflammatory. Interestingly, the percentage of mesenchymal fibroblast subpopulation is significantly increased in keloid compared to normal scar. Functional studies indicate that mesenchymal fibroblasts are crucial for collagen overexpression in keloid. Increased mesenchymal fibroblast subpopulation is also found in another fibrotic skin disease, scleroderma, suggesting this is a broad mechanism for skin fibrosis. These findings will help us better understand skin fibrotic pathogenesis, and provide potential targets for fibrotic disease therapies.
A method for measuring the molecular ratio of inhalation to exhalation and effect of inspired oxygen levels on oxygen consumption
Authors: Shinozaki Koichiro , Okuma Yu , Saeki Kota , Miyara Santiago J. , Aoki Tomoaki , Molmenti Ernesto P. , Yin Tai , Kim Junhwan , Lampe Joshua W. , Becker Lance B. 
Published: June 2021

AbstractUsing a new method for measuring the molecular ratio (R) of inhalation to exhalation, we investigated the effect of high fraction of inspired oxygen (FIO2) on oxygen consumption (VO2), carbon dioxide generation (VCO2), and respiratory quotient (RQ) in mechanically ventilated rats. Twelve rats were equally assigned into two groups by anesthetics: intravenous midazolam/fentanyl vs. inhaled isoflurane. R, VO2, VCO2, and RQ were measured at FIO2 0.3 or 1.0. R error was ± 0.003. R was 1.0099 ± 0.0023 with isoflurane and 1.0074 ± 0.0018 with midazolam/fentanyl. R was 1.0081 ± 0.0017 at an FIO2 of 0.3 and 1.0092 ± 0.0029 at an FIO2 of 1.0. There were no differences in VCO2 among the groups. VO2 increased at FIO2 1.0, which was more notable when midazolam/fentanyl was used (isoflurane-FIO2 0.3: 15.4 ± 1.1; isoflurane-FIO2 1.0: 17.2 ± 1.8; midazolam/fentanyl-FIO2 0.3: 15.4 ± 1.1; midazolam/fentanyl-FIO2 1.0: 21.0 ± 2.2 mL/kg/min at STP). The RQ was lower at FIO2 1.0 than FIO2 0.3 (isoflurane-FIO2 0.3: 0.80 ± 0.07; isoflurane-FIO2 1.0: 0.71 ± 0.05; midazolam/fentanyl-FIO2 0.3: 0.79 ± 0.03; midazolam/fentanyl-FIO2 1.0: 0.59 ± 0.04). R was not affected by either anesthetics or FIO2. Inspired 100% O2 increased VO2 and decreased RQ, which might be more remarkable when midazolam/fentanyl was used.