bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome editing in primary cells and in vivo using viral-derived Nanoblades loaded with Cas9-sgRNA ribonucleoproteins
Authors: Mangeot Philippe E. , Risson Valérie , Fusil Floriane , Marnef Aline , Laurent Emilie , Blin Juliana , Mournetas Virginie , Massouridès Emmanuelle , Sohier Thibault J. M. , Corbin Antoine , Aubé Fabien , Teixeira Marie , Pinset Christian , Schaeffer Laurent , Legube Gaëlle , Cosset François-Loïc , Verhoeyen Els , Ohlmann Théophile , Ricci Emiliano P. 
Published: December 2018

AbstractProgrammable nucleases have enabled rapid and accessible genome engineering in eukaryotic cells and living organisms. However, their delivery into target cells can be technically challenging when working with primary cells or in vivo. Here, we use engineered murine leukemia virus-like particles loaded with Cas9-sgRNA ribonucleoproteins (Nanoblades) to induce efficient genome-editing in cell lines and primary cells including human induced pluripotent stem cells, human hematopoietic stem cells and mouse bone-marrow cells. Transgene-free Nanoblades are also capable of in vivo genome-editing in mouse embryos and in the liver of injected mice. Nanoblades can be complexed with donor DNA for “all-in-one” homology-directed repair or programmed with modified Cas9 variants to mediate transcriptional up-regulation of target genes. Nanoblades preparation process is simple, relatively inexpensive and can be easily implemented in any laboratory equipped for cellular biology.
Desymmetrization of meso-bisphosphates using copper catalysis and alkylzirconocene nucleophiles
Authors: Jacques Reece , Pullin Robert D. C. , Fletcher Stephen P. 
Published: December 2018

AbstractThe desymmetrization of meso-compounds is a useful synthetic method, as illustrated by numerous applications of this strategy in natural product synthesis. Cu-catalyzed allylic desymmetrizations enable the enantioselective formation of carbon-carbon bonds, but these transformations are limited in substrate scope and by the use of highly reactive premade organometallic reagents at cryogenic temperatures. Here we show that diverse meso-bisphosphates in combination with alkylzirconium nucleophiles undergo highly regio-, diastereo- and enantio-selective Cu-catalyzed desymmetrization reactions. In addition, C2-symmetric chiral bisphosphates undergo stereospecific reactions and a racemic substrate undergoes a Cu-catalyzed kinetic resolution. The reaction tolerates functional groups incompatible with many common organometallic reagents and provides access to a broad range of functionalized carbo- and hetero-cyclic structures. The products bear up to three contiguous stereogenic centers, including quaternary centers and spirocyclic ring systems. We anticipate that the method will be a useful complement to existing catalytic enantioselective reactions.
Role of APS reductase in biogeochemical sulfur isotope fractionation
Authors: Sim Min Sub , Ogata Hideaki , Lubitz Wolfgang , Adkins Jess F. , Sessions Alex L. , Orphan Victoria J. , McGlynn Shawn E. 
Published: December 2018

AbstractSulfur isotope fractionation resulting from microbial sulfate reduction (MSR) provides some of the earliest evidence of life, and secular variations in fractionation values reflect changes in biogeochemical cycles. Here we determine the sulfur isotope effect of the enzyme adenosine phosphosulfate reductase (Apr), which is present in all known organisms conducting MSR and catalyzes the first reductive step in the pathway and reinterpret the sedimentary sulfur isotope record over geological time. Small fractionations may be attributed to low sulfate concentrations and/or high respiration rates, whereas fractionations greater than that of Apr require a low chemical potential at that metabolic step. Since Archean sediments lack fractionation exceeding the Apr value of 20‰, they are indicative of sulfate reducers having had access to ample electron donors to drive their metabolisms. Large fractionations in post-Archean sediments are congruent with a decline of favorable electron donors as aerobic and other high potential metabolic competitors evolved.
PRMT5 is essential for B cell development and germinal center dynamics
Authors: Litzler Ludivine C. , Zahn Astrid , Meli Alexandre P. , Hébert Steven , Patenaude Anne-Marie , Methot Stephen P. , Sprumont Adrien , Bois Thérence , Kitamura Daisuke , Costantino Santiago , King Irah L. , Kleinman Claudia L. , Richard Stéphane , Di Noia Javier M. 
Published: December 2018

AbstractMechanisms regulating B cell development, activation, education in the germinal center (GC) and differentiation, underpin the humoral immune response. Protein arginine methyltransferase 5 (Prmt5), which catalyzes most symmetric dimethyl arginine protein modifications, is overexpressed in B cell lymphomas but its function in normal B cells is poorly defined. Here we show that Prmt5 is necessary for antibody responses and has essential but distinct functions in all proliferative B cell stages in mice. Prmt5 is necessary for B cell development by preventing p53-dependent and p53-independent blocks in Pro-B and Pre-B cells, respectively. By contrast, Prmt5 protects, via p53-independent pathways, mature B cells from apoptosis during activation, promotes GC expansion, and counters plasma cell differentiation. Phenotypic and RNA-seq data indicate that Prmt5 regulates GC light zone B cell fate by regulating transcriptional programs, achieved in part by ensuring RNA splicing fidelity. Our results establish Prmt5 as an essential regulator of B cell biology.
Molecular memory with downstream logic processing exemplified by switchable and self-indicating guest capture and release
Authors: Daly Brian , Moody Thomas S. , Huxley Allen J. M. , Yao Chaoyi , Schazmann Benjamin , Alves-Areias Andre , Malone John F. , Gunaratne H. Q. Nimal , Nockemann Peter , de Silva A. Prasanna 
Published: December 2018

AbstractMolecular-logic based computation (MLBC) has grown by accumulating many examples of combinational logic gates and a few sequential variants. In spite of many inspirations being available in biology, there are virtually no examples of MLBC in chemistry where sequential and combinational operations are integrated. Here we report a simple alcohol-ketone redox interconversion which switches a macrocycle between a large or small cavity, with erect aromatic walls which create a deep hydrophobic space or with collapsed walls respectively. Small aromatic guests can be captured or released in an all or none manner upon chemical command. During capture, the fluorescence of the alcohol macrocycle is quenched via fluorescent photoinduced electron transfer switching, meaning that its occupancy state is self-indicated. This represents a chemically-driven RS Flip-Flop, one of whose outputs is fed into an INHIBIT gate. Processing of outputs from memory stores is seen in the injection of packaged neurotransmitters into synaptic clefts for onward neural signalling. Overall, capture-release phenomena from discrete supermolecules now have a Boolean basis.
Structural insights into trans-histone regulation of H3K4 methylation by unique histone H4 binding of MLL3/4
Authors: Liu Yanli , Qin Su , Chen Tsai-Yu , Lei Ming , Dhar Shilpa S. , Ho Jolene Caifeng , Dong Aiping , Loppnau Peter , Li Yanjun , Lee Min Gyu , Min Jinrong 
Published: December 2018

AbstractMLL3 and MLL4 are two closely related members of the SET1/MLL family of histone H3K4 methyltransferases and are responsible for monomethylating histone H3K4 on enhancers, which are essential in regulating cell-type-specific gene expression. Mutations of MLL3 or MLL4 have been reported in different types of cancer. Recently, the PHD domains of MLL3/4 have been reported to recruit the MLL3/4 complexes to their target genes by binding to histone H4 during the NT2/D1 stem cell differentiation. Here we show that an extended PHD domain (ePHD6) involving the sixth PHD domain and its preceding zinc finger in MLL3 and MLL4 specifically recognizes an H4H18-containing histone H4 fragment and that modifications of residues surrounding H4H18 modulate H4 binding to MLL3/4. Our in vitro methyltransferase assays and cellular experiments further reveal that the interaction between ePHD6 of MLL3/4 and histone H4 is required for their nucleosomal methylation activity and MLL4-mediated neuronal differentiation of NT2/D1 cells.
The non-canonical SMC protein SmcHD1 antagonises TAD formation and compartmentalisation on the inactive X chromosome
Authors: Gdula Michal R. , Nesterova Tatyana B. , Pintacuda Greta , Godwin Jonathan , Zhan Ye , Ozadam Hakan , McClellan Michael , Moralli Daniella , Krueger Felix , Green Catherine M. , Reik Wolf , Kriaucionis Skirmantas , Heard Edith , Dekker Job , Brockdorff Neil 
Published: December 2018

AbstractThe inactive X chromosome (Xi) in female mammals adopts an atypical higher-order chromatin structure, manifested as a global loss of local topologically associated domains (TADs), A/B compartments and formation of two mega-domains. Here we demonstrate that the non-canonical SMC family protein, SmcHD1, which is important for gene silencing on Xi, contributes to this unique chromosome architecture. Specifically, allelic mapping of the transcriptome and epigenome in SmcHD1 mutant cells reveals the appearance of sub-megabase domains defined by gene activation, CpG hypermethylation and depletion of Polycomb-mediated H3K27me3. These domains, which correlate with sites of SmcHD1 enrichment on Xi in wild-type cells, additionally adopt features of active X chromosome higher-order chromosome architecture, including A/B compartments and partial restoration of TAD boundaries. Xi chromosome architecture changes also occurred following SmcHD1 knockout in a somatic cell model, but in this case, independent of Xi gene derepression. We conclude that SmcHD1 is a key factor in defining the unique chromosome architecture of Xi.
Model-based lesion mapping of cognitive control using the Wisconsin Card Sorting Test
Authors: Gläscher Jan , Adolphs Ralph , Tranel Daniel 
Published: December 2018

AbstractThe role of the frontal lobes in cognition and behavior has long been enigmatic. Over the past decade, computational models have provided a powerful approach to understanding cognition and decision-making. Here, we used a model-based approach to analyze data from a classical task used to assess frontal lobe function, the Wisconsin Card Sorting Test. We applied computational modeling and voxel-based lesion-symptom mapping in 328 patients with focal lesions, to uncover cognitive processes and neural correlates of test scores. Our results reveal that lesions in the right prefrontal cortex are associated with elevated perseverative errors and reductions in the model parameter of sensitivity to punishment. These findings indicate that the capacity to flexibly switch between task sets requires the detection of contingency changes, which are enabled by a sensitivity to punishment that reduces perseverative errors. We demonstrate the power of model-based approaches in understanding patterns of deficits on classical neuropsychological tasks.
Longevity defined as top 10% survivors and beyond is transmitted as a quantitative genetic trait
Authors: van den Berg Niels , Rodríguez-Girondo Mar , van Dijk Ingrid K. , Mourits Rick J. , Mandemakers Kees , Janssens Angelique A. P. O. , Beekman Marian , Smith Ken R. , Slagboom P. Eline 
Published: December 2018

AbstractSurvival to extreme ages clusters within families. However, identifying genetic loci conferring longevity and low morbidity in such longevous families is challenging. There is debate concerning the survival percentile that best isolates the genetic component in longevity. Here, we use three-generational mortality data from two large datasets, UPDB (US) and LINKS (Netherlands). We study 20,360 unselected families containing index persons, their parents, siblings, spouses, and children, comprising 314,819 individuals. Our analyses provide strong evidence that longevity is transmitted as a quantitative genetic trait among survivors up to the top 10% of their birth cohort. We subsequently show a survival advantage, mounting to 31%, for individuals with top 10% surviving first and second-degree relatives in both databases and across generations, even in the presence of non-longevous parents. To guide future genetic studies, we suggest to base case selection on top 10% survivors of their birth cohort with equally long-lived family members.
Structure of BAI1/ELMO2 complex reveals an action mechanism of adhesion GPCRs via ELMO family scaffolds
Authors: Weng Zhuangfeng , Situ Chenghao , Lin Lin , Wu Zhenguo , Zhu Jinwei , Zhang Rongguang 
Published: December 2018

AbstractThe brain-specific angiogenesis inhibitor (BAI) subfamily of adhesion G protein-coupled receptors (aGPCRs) plays crucial roles in diverse cellular processes including phagocytosis, myoblast fusion, and synaptic development through the ELMO/DOCK/Rac signaling pathway, although the underlying molecular mechanism is not well understood. Here, we demonstrate that an evolutionarily conserved fragment located in the C-terminal cytoplasmic tail of BAI-aGPCRs is specifically recognized by the RBD-ARR-ELMO (RAE) supramodule of the ELMO family scaffolds. The crystal structures of ELMO2-RAE and its complex with BAI1 uncover the molecular basis of BAI/ELMO interactions. Based on the complex structure we identify aGPCR-GPR128 as another upstream receptor for the ELMO family scaffolds, most likely with a recognition mode similar to that of BAI/ELMO interactions. Finally, we map disease-causing mutations of BAI and ELMO and analyze their effects on complex formation.
Highly stable and efficient all-inorganic lead-free perovskite solar cells with native-oxide passivation
Authors: Chen Min , Ju Ming-Gang , Garces Hector F. , Carl Alexander D. , Ono Luis K. , Hawash Zafer , Zhang Yi , Shen Tianyi , Qi Yabing , Grimm Ronald L. , Pacifici Domenico , Zeng Xiao Cheng , Zhou Yuanyuan , Padture Nitin P. 
Published: December 2018

AbstractThere has been an urgent need to eliminate toxic lead from the prevailing halide perovskite solar cells (PSCs), but the current lead-free PSCs are still plagued with the critical issues of low efficiency and poor stability. This is primarily due to their inadequate photovoltaic properties and chemical stability. Herein we demonstrate the use of the lead-free, all-inorganic cesium tin-germanium triiodide (CsSn0.5Ge0.5I3) solid-solution perovskite as the light absorber in PSCs, delivering promising efficiency of up to 7.11%. More importantly, these PSCs show very high stability, with less than 10% decay in efficiency after 500 h of continuous operation in N2 atmosphere under one-sun illumination. The key to this striking performance of these PSCs is the formation of a full-coverage, stable native-oxide layer, which fully encapsulates and passivates the perovskite surfaces. The native-oxide passivation approach reported here represents an alternate avenue for boosting the efficiency and stability of lead-free PSCs.
Endovascular progenitors infiltrate melanomas and differentiate towards a variety of vascular beds promoting tumor metastasis
Authors: Donovan Prudence , Patel Jatin , Dight James , Wong Ho Yi , Sim Seen-Ling , Murigneux Valentine , Francois Mathias , Khosrotehrani Kiarash 
Published: December 2018

AbstractTumor vascularization is a hallmark of cancer central to disease progression and metastasis. Current anti-angiogenic therapies have limited success prompting the need to better understand the cellular origin of tumor vessels. Using fate-mapping analysis of endothelial cell populations in melanoma, we report the very early infiltration of endovascular progenitors (EVP) in growing tumors. These cells harbored self-renewal and reactivated the expression of SOX18 transcription factor, initiating a vasculogenic process as single cells, progressing towards a transit amplifying stage and ultimately differentiating into more mature endothelial phenotypes that comprised arterial, venous and lymphatic subtypes within the core of the tumor. Molecular profiling by RNA sequencing of purified endothelial fractions characterized EVPs as quiescent progenitors remodeling the extracellular matrix with significant paracrine activity promoting growth. Functionally, EVPs did not rely on VEGF-A signaling whereas endothelial-specific loss ofRbpjdepleted the population and strongly inhibited metastasis. The understanding of endothelial heterogeneity opens new avenues for more effective anti-vascular therapies in cancer.
Completion of the cytosolic post-chorismate phenylalanine biosynthetic pathway in plants
Authors: Qian Yichun , Lynch Joseph H. , Guo Longyun , Rhodes David , Morgan John A. , Dudareva Natalia 
Published: December 2018

AbstractIn addition to being a vital component of proteins, phenylalanine is also a precursor of numerous aromatic primary and secondary metabolites with broad physiological functions. In plants phenylalanine is synthesized predominantly via the arogenate pathway in plastids. Here, we describe the structure, molecular players and subcellular localization of a microbial-like phenylpyruvate pathway for phenylalanine biosynthesis in plants. Using a reverse genetic approach and metabolic flux analysis, we provide evidence that the cytosolic chorismate mutase is responsible for directing carbon flux towards cytosolic phenylalanine production via the phenylpyruvate pathway. We also show that an alternative transcription start site of a known plastidial enzyme produces a functional cytosolic prephenate dehydratase that catalyzes the conversion of prephenate to phenylpyruvate, the intermediate step between chorismate mutase and phenylpyruvate aminotransferase. Thus, our results complete elucidation of phenylalanine biosynthesis via phenylpyruvate in plants, showing that this pathway splits from the known plastidial arogenate pathway at chorismate, instead of prephenate as previously thought, and the complete pathway is localized in the cytosol.
CRISPR/Cas9 editing of APP C-terminus attenuates β-cleavage and promotes α-cleavage
Authors: Sun Jichao , Carlson-Stevermer Jared , Das Utpal , Shen Minjie , Delenclos Marion , Snead Amanda M. , Koo So Yeon , Wang Lina , Qiao Dianhua , Loi Jonathan , Petersen Andrew J. , Stockton Michael , Bhattacharyya Anita , Jones Mathew V. , Zhao Xinyu , McLean Pamela J. , Sproul Andrew A. , Saha Krishanu , Roy Subhojit 
Published: December 2018

AbstractCRISPR/Cas9 guided gene-editing is a potential therapeutic tool, however application to neurodegenerative disease models has been limited. Moreover, conventional mutation correction by gene-editing would only be relevant for the small fraction of neurodegenerative cases that are inherited. Here we introduce a CRISPR/Cas9-based strategy in cell and animal models to edit endogenous amyloid precursor protein (APP) at the extreme C-terminus and reciprocally manipulate the amyloid pathway, attenuating APP-β-cleavage and Aβ production, while up-regulating neuroprotective APP-α-cleavage. APP N-terminus and compensatory APP-homologues remain intact, with no apparent effects on neurophysiology in vitro. Robust APP-editing is seen in human iPSC-derived neurons and mouse brains with no detectable off-target effects. Our strategy likely works by limiting APP and BACE-1 approximation, and we also delineate mechanistic events that abrogates APP/BACE-1 convergence in this setting. Our work offers conceptual proof for a selective APP silencing strategy.
Low-frequency vibrational modes of stable glasses
Authors: Wang Lijin , Ninarello Andrea , Guan Pengfei , Berthier Ludovic , Szamel Grzegorz , Flenner Elijah 
Published: December 2018

AbstractUnusual features of the vibrational density of states D(ω) of glasses allow one to rationalize their peculiar low-temperature properties. Simulational studies of D(ω) have been restricted to studying poorly annealed glasses that may not be relevant to experiments. Here we report on D(ω) of zero-temperature glasses with kinetic stabilities ranging from poorly annealed to ultrastable glasses. For all preparations, the low-frequency part of D(ω) splits between extended and quasi-localized modes. Extended modes exhibit a boson peak crossing over to Debye behavior (Dex(ω) ~ ω2) at low-frequency, with a strong correlation between the two regimes. Quasi-localized modes obey Dloc(ω) ~ ω4, irrespective of the stability. The prefactor of this quartic law decreases with increasing stability, and the corresponding modes become more localized and sparser. Our work is the first numerical observation of quasi-localized modes in a regime relevant to experiments, and it establishes a direct connection between glasses’ stability and their soft vibrational modes
Transposable elements are regulated by context-specific patterns of chromatin marks in mouse embryonic stem cells
Authors: He Jiangping , Fu Xiuling , Zhang Meng , He Fangfang , Li Wenjuan , Abdul Mazid Md. , Zhou Jianguo , Sun Li , Chang Chen , Li Yuhao , Liu He , Wu Kaixin , Babarinde Isaac A. , Zhuang Qiang , Loh Yuin-Han , Chen Jiekai , Esteban Miguel A. , Hutchins Andrew P. 
Published: December 2018

AbstractThe majority of mammalian genomes are devoted to transposable elements (TEs). Whilst TEs are increasingly recognized for their important biological functions, they are a potential danger to genomic stability and are carefully regulated by the epigenetic system. However, the full complexity of this regulatory system is not understood. Here, using mouse embryonic stem cells, we show that TEs are suppressed by heterochromatic marks like H3K9me3, and are also labelled by all major types of chromatin modification in complex patterns, including bivalent activatory and repressive marks. We identified 29 epigenetic modifiers that significantly deregulated at least one type of TE. The loss of Setdb1, Ncor2, Rnf2, Kat5, Prmt5, Uhrf1, and Rrp8 caused widespread changes in TE expression and chromatin accessibility. These effects were context-specific, with different chromatin modifiers regulating the expression and chromatin accessibility of specific subsets of TEs. Our work reveals the complex patterns of epigenetic regulation of TEs.
Manifold learning of four-dimensional scanning transmission electron microscopy
Authors: Li Xin , Dyck Ondrej E. , Oxley Mark P. , Lupini Andrew R. , McInnes Leland , Healy John , Jesse Stephen , Kalinin Sergei V. 
Published: December 2018

AbstractFour-dimensional scanning transmission electron microscopy (4D-STEM) of local atomic diffraction patterns is emerging as a powerful technique for probing intricate details of atomic structure and atomic electric fields. However, efficient processing and interpretation of large volumes of data remain challenging, especially for two-dimensional or light materials because the diffraction signal recorded on the pixelated arrays is weak. Here we employ data-driven manifold leaning approaches for straightforward visualization and exploration analysis of 4D-STEM datasets, distilling real-space neighboring effects on atomically resolved deflection patterns from single-layer graphene, with single dopant atoms, as recorded on a pixelated detector. These extracted patterns relate to both individual atom sites and sublattice structures, effectively discriminating single dopant anomalies via multi-mode views. We believe manifold learning analysis will accelerate physics discoveries coupled between data-rich imaging mechanisms and materials such as ferroelectric, topological spin, and van der Waals heterostructures.