Recurrent deletions of ULK4 in schizophrenia : a gene crucial for neuritogenesis and neuronal motility

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Systems-Based Design of Bi-Ligand Inhibitors of Oxidoreductases: Filling the Chemical Proteomic Toolbox

Genomics-driven growth in the number of enzymes of unknown function has created a need for better strategies to characterize them. Since enzyme inhibitors have traditionally served this purpose, we present here an efficient systems-based inhibitor design strategy, enabled by bioinformatic and NMR structural developments. First, we parse the oxidoreductase gene family into structural subfamilies termed pharmacofamilies, which share pharmacophore features in their cofactor binding sites. Then we identify a ligand for this site and use NMR-based binding site mapping (NMR SOLVE) to determine where to extend a combinatorial library, such that diversity elements are directed into the adjacent substrate site. The cofactor mimic is reused in the library in a manner that parallels the reuse of cofactor domains in the oxidoreductase gene family. A library designed in this manner yielded specific inhibitors for multiple oxidoreductases

Rare earth magnetism in CeFeAsO: A single crystal study

Single crystals of CeFeAsO, large enough to study the anisotropy of the magnetic properties, were grown by an optimized Sn-flux technique. The high quality of our single crystals is apparent from the highest residual resistivity ratio, RRR = 12, reported among undoped RFeAsO compounds (R=rare earth) as well as sharp anomalies in resistivity, specific heat, C(T), and thermal expansion at the different phase transitions. The magnetic susceptibility chi(T) presents a large easy-plane anisotropy consistent with the lowest crystal electric field doublet having a dominant Gamma_6 character. Curie-Weiss like susceptibilities for magnetic field parallel and perpendicular to the crystallographic c-axis do not reveal an influence of a staggered field on the Ce site induced by magnetic ordering of the Fe. Furthermore, the standard signatures for antiferromagnetic order of Ce at T_N = 3.7 K observed in chi(T) and C(T) are incompatible with a Zeeman splitting Delta = 10 K of the CEF ground state doublet at low temperature due to the Fe-magnetic order as previously proposed. Our results can be reconciled with the earlier observation by assuming a comparatively stronger effect of the Ce-Ce exchange leading to a reduction of this Zeeman splitting below 15 K.Comment: 15 pages, 6 figures, added section on magn. susceptibilit

Lithofacies Characteristics and Sweet Spot Distribution of Lacustrine Shale Oil: A Case Study from the Dongying Depression, Bohai Bay Basin, China

AbstractLacustrine shale is characterized by rapid lithofacies transformation and compositional heterogeneity, which present challenges in shale oil sweet spot evaluation and distribution prediction and should be systematically studied. Field emission-scanning electron microscopy (FE-SEM), low-pressure adsorption isotherm analysis, mercury intrusion porosimetry (MIP), and triaxial compression testing were employed to comprehensively analyze the oil-bearing capacity, reservoir properties, fluidity, and frackability of different lithofacies. Via analyses of mineral composition, total organic carbon (TOC) content, and sedimentary structure, seven lithofacies were identified: organic-rich calcareous shale (L1), organic-rich laminated calcareous mudstone (L2), organic-rich laminated carbonate-bearing mudstone (L3), intermediate-organic laminated calcareous mudstone (L4), organic-poor laminated calcareous mudstone (L5), organic-poor thin-bedded calcareous mudstone (L6), and organic-rich laminated silty mudstone (L7). Considered together, the oil-bearing capacity, reservoir properties, fluidity, and frackability suggested that the L1 and L7 lithofacies were high-quality sweet spots, with satisfactory oil-bearing capacity (TOC>3.5%; S1>10 mgHC/grock), well-developed pores and microfractures, notable fluidity (as indicated by a high oil saturation index value), and suitable brittleness. The sweet spot distribution was predicted according to multiresolution graph-based clustering analysis of well logs. The results indicate that comprehensive research of the key factors for shale oil and lithofacies prediction can promote sweet spot prediction and enhance shale oil exploration

A mouse line for inducible and reversible silencing of specific neurons

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Acknowledgements: We thank Dr. Joseph W. Lynch for sharing the IVMR plasmid, and Dr. Lisa M. Monteggia for sharing the AAV2-Cre plasmid. Rosa-CAG targeting vector was obtained from Addgenes. This work was supported by the Key State Research Program from Ministry of Science and Technology of China (2011CB510005, 2012CB966900, 2013CB835103), National Natural Science Foundation of China (81221001, 81200692, 81101026, 31100788, 31271182, 31030034, 91232724), Science and Technology Commission of Shanghai Municipality (12XD1404800), Shanghai Pujiang Program (12PJ1408800), Key Disciplines Group Construction Project of Pudong Health Bureau of Shanghai (PWZxq2014-04) and Sino-UK Higher Education Research Partnership for PhD Studies.Peer reviewedPublisher PD

Dense infraspecific sampling reveals cryptic differentiation in the enigmatic hemiparasitic love vine Cassytha filiformis (Lauraceae)

Species delimitation remains a challenge worldwide, especially in highly diverse tropical and subtropical regions. Here, we use an integrative approach that combines morphology, phylogenomics, and species distribution modeling (SDM) to clarify the cryptic differentiation within the enigmatic hemiparasitic love vine Cassytha filiformis (Lauraceae) in China and adjacent regions. We generated complete plastid genomes and nuclear ribosomal sequences for diverse samples from across the species range and compared results with previously published plastid data, recovering two well-supported monophyletic clades. Further, the analysis revealed significant differences in two morphological characters and SDM, indicating distinct environmental factors influencing their distributions. Fossil-calibrated analyses to estimate the origins and diversification patterns for the cryptic species gave divergence age estimates corresponding to the Oligo-Miocene; a period of new ecological opportunities associated with the prevailing East Asian monsoon. Multivariate analyses support the conclusion that southern China and adjacent regions have a different, previously unknown, cryptic lineage of C. filiformis. Our study highlights the importance of using multivariate approach to characterize plant species, as well as the significant role that past climatic changes have played in driving speciation in parasitic plants in tropical and subtropical zones.</p

ALS/FTD Mutation-Induced Phase Transition of FUS Liquid Droplets and Reversible Hydrogels into Irreversible Hydrogels Impairs RNP Granule Function.

The mechanisms by which mutations in FUS and other RNA binding proteins cause ALS and FTD remain controversial. We propose a model in which low-complexity (LC) domains of FUS drive its physiologically reversible assembly into membrane-free, liquid droplet and hydrogel-like structures. ALS/FTD mutations in LC or non-LC domains induce further phase transition into poorly soluble fibrillar hydrogels distinct from conventional amyloids. These assemblies are necessary and sufficient for neurotoxicity in a C. elegans model of FUS-dependent neurodegeneration. They trap other ribonucleoprotein (RNP) granule components and disrupt RNP granule function. One consequence is impairment of new protein synthesis by cytoplasmic RNP granules in axon terminals, where RNP granules regulate local RNA metabolism and translation. Nuclear FUS granules may be similarly affected. Inhibiting formation of these fibrillar hydrogel assemblies mitigates neurotoxicity and suggests a potential therapeutic strategy that may also be applicable to ALS/FTD associated with mutations in other RNA binding proteins.Supported by Canadian Institutes of Health Research (PEF, PStGH), Alzheimer Society of Ontario (PEF, PStGH), Wellcome Trust (PStGH, MEV, CFK, GSK, DR, CEH), Medical Research Council (PStGH, MEV, CFK, GSK), National Institutes of Health Research, Alzheimer Research UK (CFK, GSK), Gates Cambridge Scholarship (JQL), Engineering and Physical Sciences Research Council (CFK, GSK), European Research Council Starting Grant RIBOMYLOME_309545 (GGT), European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013) / ERC Grant Agreement no. 322817 (CEH), and National Institute of Neurological Disorders and Stroke R01 NS07377 (NAS). The authors thank Tom Cech and Roy Parker for helpful discussions.This is the final version of the article. It was first available from Elsevier via http://dx.doi.org/10.1016/j.neuron.2015.10.03

High-Performance Flexible Quasi-Solid-State Supercapacitors Realized by Molybdenum Dioxide@Nitrogen-Doped Carbon and Copper Cobalt Sulfide Tubular Nanostructures

Flexible quasi‐/all‐solid‐state supercapacitors have elicited scientific attention to fulfill the explosive demand for portable and wearable electronic devices. However, the use of electrode materials faces several challenges, such as intrinsically slow kinetics and volume change upon cycling, which impede the energy output and electrochemical stability. This study presents well‐aligned molybdenum dioxide@nitrogen‐doped carbon (MoO2@NC) and copper cobalt sulfide (CuCo2S4) tubular nanostructures grown on flexible carbon fiber for use as electrode materials in supercapacitors. Benefiting from the chemically stable interfaces, affluent active sites, and efficient 1D electron transport, the MoO2@NC and CuCo2S4 nanostructures integrated on conductive substrates deliver excellent electrochemical performance. A flexible quasi‐solid‐state asymmetric supercapacitor composed of MoO2@NC as the negative electrode and CuCo2S4 as the positive electrode achieves an ultrahigh energy density of 65.1 W h kg−1 at a power density of 800 W kg−1 and retains a favorable energy density of 27.6 W h kg−1 at an ultrahigh power density of 12.8 kW kg−1. Moreover, it demonstrates good cycling performance with 90.6% capacitance retention after 5000 cycles and excellent mechanical flexibility by enabling 92.2% capacitance retention after 2000 bending cycles. This study provides an effective strategy to develop electrode materials with superior electrochemical performance for flexible supercapacitors

FGF2 regulates melanocytes viability through the STAT3-transactivated PAX3 transcription

PAX3 (paired box 3) is known to have an important role in melanocyte development through modulation of microphthalmia-associated transcription factor transcription. Here we found that PAX3 transcriptional activity could be regulated through FGF2 (basic fibroblast growth factor)-STAT3 (signal transducer and activator of transcription 3) signaling in the pigment cells. To study its function in vivo, we have generated a transgenic mouse model expressing PAX3 driven by tyrosinase promoter in a tissue-specific fashion. These animals exhibit hyperpigmentation in the epidermis, evident in the skin color of their ears and tails. We showed that the darker skin color results from both increased melanocyte numbers and melanin synthesis. Together, our study delineated a novel pathway in the melanocyte lineage, linking FGF2-STAT3 signaling to increased PAX3 transcription. Moreover, our results suggest that this pathway might contribute to the regulation of melanocyte numbers and melanin levels, and thereby provide an alternative strategy to induce pigmentation