bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hakai is required for stabilization of core components of the m6A mRNA methylation machinery
Authors: Bawankar Praveen , Lence Tina , Paolantoni Chiara , Haussmann Irmgard U. , Kazlauskiene Migle , Jacob Dominik , Heidelberger Jan B. , Richter Florian M. , Nallasivan Mohanakarthik P. , Morin Violeta , Kreim Nastasja , Beli Petra , Helm Mark , Jinek Martin , Soller Matthias , Roignant Jean-Yves 
Published: June 2021

AbstractN6-methyladenosine (m6A) is the most abundant internal modification on mRNA which influences most steps of mRNA metabolism and is involved in several biological functions. The E3 ubiquitin ligase Hakai was previously found in complex with components of the m6A methylation machinery in plants and mammalian cells but its precise function remained to be investigated. Here we show that Hakai is a conserved component of the methyltransferase complex in Drosophila and human cells. In Drosophila, its depletion results in reduced m6A levels and altered m6A-dependent functions including sex determination. We show that its ubiquitination domain is required for dimerization and interaction with other members of the m6A machinery, while its catalytic activity is dispensable. Finally, we demonstrate that the loss of Hakai destabilizes several subunits of the methyltransferase complex, resulting in impaired m6A deposition. Our work adds functional and molecular insights into the mechanism of the m6A mRNA writer complex.
Community factors and excess mortality in first wave of the COVID-19 pandemic in England
Authors: Davies Bethan , Parkes Brandon L. , Bennett James , Fecht Daniela , Blangiardo Marta , Ezzati Majid , Elliott Paul 
Published: June 2021

AbstractRisk factors for increased risk of death from COVID-19 have been identified, but less is known on characteristics that make communities resilient or vulnerable to the mortality impacts of the pandemic. We applied a two-stage Bayesian spatial model to quantify inequalities in excess mortality in people aged 40 years and older at the community level during the first wave of the pandemic in England, March-May 2020 compared with 2015–2019. Here we show that communities with an increased risk of excess mortality had a high density of care homes, and/or high proportion of residents on income support, living in overcrowded homes and/or with a non-white ethnicity. We found no association between population density or air pollution and excess mortality. Effective and timely public health and healthcare measures that target the communities at greatest risk are urgently needed to avoid further widening of inequalities in mortality patterns as the pandemic progresses.
Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action
Authors: Kast Florian , Schwill Martin , Stüber Jakob C. , Pfundstein Svende , Nagy-Davidescu Gabriela , Rodríguez Josep M. Monné , Seehusen Frauke , Richter Christian P. , Honegger Annemarie , Hartmann Karen Patricia , Weber Thomas G. , Kroener Felix , Ernst Patrick , Piehler Jacob , Plückthun Andreas 
Published: June 2021

AbstractThe receptor tyrosine kinase HER2 acts as oncogenic driver in numerous cancers. Usually, the gene is amplified, resulting in receptor overexpression, massively increased signaling and unchecked proliferation. However, tumors become frequently addicted to oncogenes and hence are druggable by targeted interventions. Here, we design an anti-HER2 biparatopic and tetravalent IgG fusion with a multimodal mechanism of action. The molecule first induces HER2 clustering into inactive complexes, evidenced by reduced mobility of surface HER2. However, in contrast to our earlier binders based on DARPins, clusters of HER2 are thereafter robustly internalized and quantitatively degraded. This multimodal mechanism of action is found only in few of the tetravalent constructs investigated, which must target specific epitopes on HER2 in a defined geometric arrangement. The inhibitory effect of our antibody as single agent surpasses the combination of trastuzumab and pertuzumab as well as its parental mAbs in vitro and it is effective in a xenograft model.
High-throughput screening and rational design of biofunctionalized surfaces with optimized biocompatibility and antimicrobial activity
Authors: Fang Zhou , Chen Junjian , Zhu Ye , Hu Guansong , Xin Haoqian , Guo Kunzhong , Li Qingtao , Xie Liangxu , Wang Lin , Shi Xuetao , Wang Yingjun , Mao Chuanbin 
Published: June 2021

AbstractPeptides are widely used for surface modification to develop improved implants, such as cell adhesion RGD peptide and antimicrobial peptide (AMP). However, it is a daunting challenge to identify an optimized condition with the two peptides showing their intended activities and the parameters for reaching such a condition. Herein, we develop a high-throughput strategy, preparing titanium (Ti) surfaces with a gradient in peptide density by click reaction as a platform, to screen the positions with desired functions. Such positions are corresponding to optimized molecular parameters (peptide densities/ratios) and associated preparation parameters (reaction times/reactant concentrations). These parameters are then extracted to prepare nongradient mono- and dual-peptide functionalized Ti surfaces with desired biocompatibility or/and antimicrobial activity in vitro and in vivo. We also demonstrate this strategy could be extended to other materials. Here, we show that the high-throughput versatile strategy holds great promise for rational design and preparation of functional biomaterial surfaces.
Highly metastatic claudin-low mammary cancers can originate from luminal epithelial cells
Authors: Rädler Patrick D. , Wehde Barbara L. , Triplett Aleata A. , Shrestha Hridaya , Shepherd Jonathan H. , Pfefferle Adam D. , Rui Hallgeir , Cardiff Robert D. , Perou Charles M. , Wagner Kay-Uwe 
Published: June 2021

AbstractClaudin-low breast cancer represents an aggressive molecular subtype that is comprised of mostly triple-negative mammary tumor cells that possess stem cell-like and mesenchymal features. Little is known about the cellular origin and oncogenic drivers that promote claudin-low breast cancer. In this study, we show that persistent oncogenic RAS signaling causes highly metastatic triple-negative mammary tumors in mice. More importantly, the activation of endogenous mutant KRAS and expression of exogenous KRAS specifically in luminal epithelial cells in a continuous and differentiation stage-independent manner induces preneoplastic lesions that evolve into basal-like and claudin-low mammary cancers. Further investigations demonstrate that the continuous signaling of oncogenic RAS, as well as regulators of EMT, play a crucial role in the cellular plasticity and maintenance of the mesenchymal and stem cell characteristics of claudin-low mammary cancer cells.
Measurement of lipogenic flux by deuterium resolved mass spectrometry
Authors: Fu Xiaorong , Deja Stanisław , Fletcher Justin A. , Anderson Norma N. , Mizerska Monika , Vale Gonçalo , Browning Jeffrey D. , Horton Jay D. , McDonald Jeffrey G. , Mitsche Matthew A. , Burgess Shawn C. 
Published: June 2021

AbstractDe novo lipogenesis (DNL) is disrupted in a wide range of human disease. Thus, quantification of DNL may provide insight into mechanisms and guide interventions if it can be performed rapidly and noninvasively. DNL flux is commonly measured by 2H incorporation into fatty acids following deuterated water (2H2O) administration. However, the sensitivity of this approach is limited by the natural abundance of 13C, which masks detection of 2H by mass spectrometry. Here we report that high-resolution Orbitrap gas-chromatography mass-spectrometry resolves 2H and 13C fatty acid mass isotopomers, allowing DNL to be quantified using lower 2H2O doses and shorter experimental periods than previously possible. Serial measurements over 24-hrs in mice detects the nocturnal activation of DNL and matches a 3H-water method in mice with genetic activation of DNL. Most importantly, DNL is detected in overnight-fasted humans in less than an hour and is responsive to feeding during a 4-h study. Thus, 2H specific MS provides the ability to study DNL in settings that are currently impractical.
Design of COVID-19 staged alert systems to ensure healthcare capacity with minimal closures
Authors: Yang Haoxiang , Sürer Özge , Duque Daniel , Morton David P. , Singh Bismark , Fox Spencer J. , Pasco Remy , Pierce Kelly , Rathouz Paul , Valencia Victoria , Du Zhanwei , Pignone Michael , Escott Mark E. , Adler Stephen I. , Johnston S. Claiborne , Meyers Lauren Ancel 
Published: June 2021

AbstractCommunity mitigation strategies to combat COVID-19, ranging from healthy hygiene to shelter-in-place orders, exact substantial socioeconomic costs. Judicious implementation and relaxation of restrictions amplify their public health benefits while reducing costs. We derive optimal strategies for toggling between mitigation stages using daily COVID-19 hospital admissions. With public compliance, the policy triggers ensure adequate intensive care unit capacity with high probability while minimizing the duration of strict mitigation measures. In comparison, we show that other sensible COVID-19 staging policies, including France’s ICU-based thresholds and a widely adopted indicator for reopening schools and businesses, require overly restrictive measures or trigger strict stages too late to avert catastrophic surges. As proof-of-concept, we describe the optimization and maintenance of the staged alert system that has guided COVID-19 policy in a large US city (Austin, Texas) since May 2020. As cities worldwide face future pandemic waves, our findings provide a robust strategy for tracking COVID-19 hospital admissions as an early indicator of hospital surges and enacting staged measures to ensure integrity of the health system, safety of the health workforce, and public confidence.
Brain structure is linked to the association between family environment and behavioral problems in children in the ABCD study
Authors: Gong Weikang , Rolls Edmund T. , Du Jingnan , Feng Jianfeng , Cheng Wei 
Published: June 2021

AbstractChildren’s behavioral problems have been associated with their family environments. Here, we investigate whether specific features of brain structures could relate to this link. Using structural magnetic resonance imaging of 8756 children aged 9-11 from the Adolescent Brain Cognitive Developmental study, we show that high family conflict and low parental monitoring scores are associated with children’s behavioral problems, as well as with smaller cortical areas of the orbitofrontal cortex, anterior cingulate cortex, and middle temporal gyrus. A longitudinal analysis indicates that psychiatric problems scores are associated with increased family conflict and decreased parental monitoring 1 year later, and mediate associations between the reduced cortical areas and family conflict, and parental monitoring scores. These results emphasize the relationships between the brain structure of children, their family environments, and their behavioral problems.
Enantioselective synthesis of tertiary boronic esters through catalytic asymmetric reversed hydroboration
Authors: Gao Tao-Tao , Lu Hou-Xiang , Gao Peng-Chao , Li Bi-Jie 
Published: June 2021

AbstractChiral tertiary boronic esters are important precursors to bioactive compounds and versatile synthetic intermediates to molecules containing quaternary stereocenters. The development of conjugate boryl addition to α,β-unsaturated amide has been hampered by the intrinsic low electrophilicity of the amide group. Here we show the catalytic asymmetric synthesis of enantioenriched tertiary boronic esters through hydroboration of β,β-disubstituted α,β-unsaturated amides. The Rh-catalyzed hydroboration occurs with previously unattainable selectivity to provide tertiary boronic esters in high enantioselectivity. This strategy opens a door for the hydroboration of inert Michael acceptors with high stereocontrol and may provide future applications in the synthesis of biologically active molecules.
Position-controlled quantum emitters with reproducible emission wavelength in hexagonal boron nitride
Authors: Fournier Clarisse , Plaud Alexandre , Roux Sébastien , Pierret Aurélie , Rosticher Michael , Watanabe Kenji , Taniguchi Takashi , Buil Stéphanie , Quélin Xavier , Barjon Julien , Hermier Jean-Pierre , Delteil Aymeric 
Published: June 2021

AbstractSingle photon emitters (SPEs) in low-dimensional layered materials have recently gained a large interest owing to the auspicious perspectives of integration and extreme miniaturization offered by this class of materials. However, accurate control of both the spatial location and the emission wavelength of the quantum emitters is essentially lacking to date, thus hindering further technological steps towards scalable quantum photonic devices. Here, we evidence SPEs in high purity synthetic hexagonal boron nitride (hBN) that can be activated by an electron beam at chosen locations. SPE ensembles are generated with a spatial accuracy better than the cubed emission wavelength, thus opening the way to integration in optical microstructures. Stable and bright single photon emission is subsequently observed in the visible range up to room temperature upon non-resonant laser excitation. Moreover, the low-temperature emission wavelength is reproducible, with an ensemble distribution of width 3 meV, a statistical dispersion that is more than one order of magnitude lower than the narrowest wavelength spreads obtained in epitaxial hBN samples. Our findings constitute an essential step towards the realization of top-down integrated devices based on identical quantum emitters in 2D materials.
Serum amyloid P component is an essential element of resistance against Aspergillus fumigatus
Authors: Doni Andrea , Parente Raffaella , Laface Ilaria , Magrini Elena , Cunha Cristina , Colombo Federico Simone , Lacerda João F. , Campos António , Mapelli Sarah N. , Petroni Francesca , Porte Rémi , Schorn Tilo , Inforzato Antonio , Mercier Toine , Lagrou Katrien , Maertens Johan , Lambris John D. , Bottazzi Barbara , Garlanda Cecilia , Botto Marina , Carvalho Agostinho , Mantovani Alberto 
Published: June 2021

AbstractSerum amyloid P component (SAP, also known as Pentraxin 2; APCS gene) is a component of the humoral arm of innate immunity involved in resistance to bacterial infection and regulation of tissue remodeling. Here we investigate the role of SAP in antifungal resistance. Apcs−/− mice show enhanced susceptibility to A. fumigatus infection. Murine and human SAP bound conidia, activate the complement cascade and enhance phagocytosis by neutrophils. Apcs−/− mice are defective in vivo in terms of recruitment of neutrophils and phagocytosis in the lungs. Opsonic activity of SAP is dependent on the classical pathway of complement activation. In immunosuppressed mice, SAP administration protects hosts against A. fumigatus infection and death. In the context of a study of hematopoietic stem-cell transplantation, genetic variation in the human APCS gene is associated with susceptibility to invasive pulmonary aspergillosis. Thus, SAP is a fluid phase pattern recognition molecule essential for resistance against A. fumigatus.
Catalyst-free carbosilylation of alkenes using silyl boronates and organic fluorides via selective C-F bond activation
Authors: Zhou Jun , Jiang Bingyao , Fujihira Yamato , Zhao Zhengyu , Imai Takanori , Shibata Norio 
Published: June 2021

AbstractA regioselective carbosilylation of alkenes has emerged as a powerful strategy to access molecules with functionalized silylated alkanes, by incorporating silyl and carbon groups across an alkene double bond. However, to the best of our knowledge, organic fluorides have never been used in this protocol. Here we disclose the catalyst-free carbosilylation of alkenes using silyl boronates and organic fluorides mediated by tBuOK. The main feature of this transformation is the selective activation of the C-F bond of an organic fluoride by the silyl boronate without undergoing potential side-reactions involving C-O, C-Cl, heteroaryl-CH, and even CF3 groups. Various silylated alkanes with tertiary or quaternary carbon centers that have aromatic, hetero-aromatic, and/or aliphatic groups at the β-position are synthesized in a single step from substituted or non-substituted aryl alkenes. An intramolecular variant of this carbosilylation is also achieved via the reaction of a fluoroarene with a ω-alkenyl side chain and a silyl boronate.
Arginine methylation of METTL14 promotes RNA N6-methyladenosine modification and endoderm differentiation of mouse embryonic stem cells
Authors: Liu Xiaona , Wang Hailong , Zhao Xueya , Luo Qizhi , Wang Qingwen , Tan Kaifen , Wang Zihan , Jiang Jia , Cui Jinru , Du Enhui , Xia Linjian , Du Wenyi , Chen Dahua , Xia Laixin , Xiao Shan 
Published: June 2021

AbstractRNA N6-methyladenosine (m6A), the most abundant internal modification of mRNAs, plays key roles in human development and health. Post-translational methylation of proteins is often critical for the dynamic regulation of enzymatic activity. However, the role of methylation of the core methyltransferase METTL3/METTL14 in m6A regulation remains elusive. We find by mass spectrometry that METTL14 arginine 255 (R255) is methylated (R255me). Global mRNA m6A levels are greatly decreased in METTL14 R255K mutant mouse embryonic stem cells (mESCs). We further find that R255me greatly enhances the interaction of METTL3/METTL14 with WTAP and promotes the binding of the complex to substrate RNA. We show that protein arginine N-methyltransferases 1 (PRMT1) interacts with and methylates METTL14 at R255, and consistent with this, loss of PRMT1 reduces mRNA m6A modification globally. Lastly, we find that loss of R255me preferentially affects endoderm differentiation in mESCs. Collectively, our findings show that arginine methylation of METTL14 stabilizes the binding of the m6A methyltransferase complex to its substrate RNA, thereby promoting global m6A modification and mESC endoderm differentiation. This work highlights the crosstalk between protein methylation and RNA methylation in gene expression.
Genome-wide association study identifies five risk loci for pernicious anemia
Authors: Laisk Triin , Lepamets Maarja , Koel Mariann , Abner Erik ,   Estonian Biobank Research Team, Metspalu Andres , Nelis Mari , Milani Lili , Esko Tõnu , Mägi Reedik 
Published: June 2021

AbstractPernicious anemia is a rare condition characterized by vitamin B12 deficiency anemia due to lack of intrinsic factor, often caused by autoimmune gastritis. Patients with pernicious anemia have a higher incidence of other autoimmune disorders, such as type 1 diabetes, vitiligo, and autoimmune thyroid issues. Therefore, the disease has a clear autoimmune basis, although the genetic susceptibility factors have thus far remained poorly studied. We conduct a genome-wide association study meta-analysis in 2166 cases and 659,516 European controls from population-based biobanks and identify genome-wide significant signals in or near the PTPN22 (rs6679677, p = 1.91 × 10−24, OR = 1.63), PNPT1 (rs12616502, p = 3.14 × 10−8, OR = 1.70), HLA-DQB1 (rs28414666, p = 1.40 × 10−16, OR = 1.38), IL2RA (rs2476491, p = 1.90 × 10−8, OR = 1.22) and AIRE (rs74203920, p = 2.33 × 10−9, OR = 1.83) genes, thus providing robust associations between pernicious anemia and genetic risk factors.
Molecular insights into ago-allosteric modulation of the human glucagon-like peptide-1 receptor
Authors: Cong Zhaotong , Chen Li-Nan , Ma Honglei , Zhou Qingtong , Zou Xinyu , Ye Chenyu , Dai Antao , Liu Qing , Huang Wei , Sun Xianqiang , Wang Xi , Xu Peiyu , Zhao Lihua , Xia Tian , Zhong Wenge , Yang Dehua , Eric Xu H. , Zhang Yan , Wang Ming-Wei 
Published: June 2021

AbstractThe glucagon-like peptide-1 (GLP-1) receptor is a validated drug target for metabolic disorders. Ago-allosteric modulators are capable of acting both as agonists on their own and as efficacy enhancers of orthosteric ligands. However, the molecular details of ago-allosterism remain elusive. Here, we report three cryo-electron microscopy structures of GLP-1R bound to (i) compound 2 (an ago-allosteric modulator); (ii) compound 2 and GLP-1; and (iii) compound 2 and LY3502970 (a small molecule agonist), all in complex with heterotrimeric Gs. The structures reveal that compound 2 is covalently bonded to C347 at the cytoplasmic end of TM6 and triggers its outward movement in cooperation with the ECD whose N terminus penetrates into the GLP-1 binding site. This allows compound 2 to execute positive allosteric modulation through enhancement of both agonist binding and G protein coupling. Our findings offer insights into the structural basis of ago-allosterism at GLP-1R and may aid the design of better therapeutics.
Multifunctional wide-angle optics and lasing based on supercell metasurfaces
Authors: Spägele Christina , Tamagnone Michele , Kazakov Dmitry , Ossiander Marcus , Piccardo Marco , Capasso Federico 
Published: June 2021

AbstractMetasurfaces are arrays of subwavelength spaced nanostructures that can manipulate the amplitude, phase, and polarization of light to achieve a variety of optical functions beyond the capabilities of 3D bulk optics. However, they suffer from limited performance and efficiency when multiple functions with large deflection angles are required because the non-local interactions due to optical coupling between nanostructures are not fully considered. Here we introduce a method based on supercell metasurfaces to demonstrate multiple independent optical functions at arbitrary large deflection angles with high efficiency. In one implementation the incident laser is simultaneously diffracted into Gaussian, helical and Bessel beams over a large angular range. We then demonstrate a compact wavelength-tunable external cavity laser with arbitrary beam control capabilities – including beam shaping operations and the generation of freeform holograms. Our approach paves the way to novel methods to engineer the emission of optical sources.
Quantum billiards with correlated electrons confined in triangular transition metal dichalcogenide monolayer nanostructures
Authors: Ravnik Jan , Vaskivskyi Yevhenii , Vodeb Jaka , Aupič Polona , Vaskivskyi Igor , Golež Denis , Gerasimenko Yaroslav , Kabanov Viktor , Mihailovic Dragan 
Published: June 2021

AbstractForcing systems through fast non-equilibrium phase transitions offers the opportunity to study new states of quantum matter that self-assemble in their wake. Here we study the quantum interference effects of correlated electrons confined in monolayer quantum nanostructures, created by femtosecond laser-induced quench through a first-order polytype structural transition in a layered transition-metal dichalcogenide material. Scanning tunnelling microscopy of the electrons confined within equilateral triangles, whose dimensions are a few crystal unit cells on the side, reveals that the trajectories are strongly modified from free-electron states both by electronic correlations and confinement. Comparison of experiments with theoretical predictions of strongly correlated electron behaviour reveals that the confining geometry destabilizes the Wigner/Mott crystal ground state, resulting in mixed itinerant and correlation-localized states intertwined on a length scale of 1 nm. The work opens the path toward understanding the quantum transport of electrons confined in atomic-scale monolayer structures based on correlated-electron-materials.