O-GlcNAc modification blocks the aggregation and toxicity of the protein α-synuclein associated with Parkinson's disease.

Several aggregation-prone proteins associated with neurodegenerative diseases can be modified by O-linked N-acetyl-glucosamine (O-GlcNAc) in vivo. One of these proteins, α-synuclein, is a toxic aggregating protein associated with synucleinopathies, including Parkinson's disease. However, the effect of O-GlcNAcylation on α-synuclein is not clear. Here, we use synthetic protein chemistry to generate both unmodified α-synuclein and α-synuclein bearing a site-specific O-GlcNAc modification at the physiologically relevant threonine residue 72. We show that this single modification has a notable and substoichiometric inhibitory effect on α-synuclein aggregation, while not affecting the membrane binding or bending properties of α-synuclein. O-GlcNAcylation is also shown to affect the phosphorylation of α-synuclein in vitro and block the toxicity of α-synuclein that was exogenously added to cells in culture. These results suggest that increasing O-GlcNAcylation may slow the progression of synucleinopathies and further support a general function for O-GlcNAc in preventing protein aggregation

Changes in body temperature and circulating levels of interleukin-6 after intra-arterial injections or infusions of tumor necrosis factor α in guinea pigs

Tumor necrosis factor α (TNF) is released systematically during the early phase of endotoxin induced fever. To study the effects of this cytokine in guinea pigs, 2 μg TNF were intra-arterially injected as a bolus or slowly infused within 60 min. Both modes of administration induced a biphasic elevation of the animals' abdominal temperature lasting 6 h and stimulated the release of endogenous interleukin-6 (IL-6)-like activity. The second phase of the thermal response and the release of endogenous IL-6-like activity were significantly higher, when TNF was slowly infused into the animals' circulation, in spite of a transiently higher TNF-like activity after the bolus injection of TNF. Both TNF and IL-6 may therefore be regarded as candidates to trigger the febrile response in guinea pigs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42862/1/18_2005_Article_BF01956462.pd

The Lyman alpha reference sample. VII. Spatially resolved Hα\alpha kinematics

We present integral field spectroscopic observations with the Potsdam Multi Aperture Spectrophotometer of all 14 galaxies in the $z\sim 0.1$ Lyman Alpha Reference Sample (LARS). We produce 2D line of sight velocity maps and velocity dispersion maps from the Balmer $\alpha$ (H$\alpha$) emission in our data cubes. These maps trace the spectral and spatial properties of the LARS galaxies' intrinsic Ly$\alpha$ radiation field. We show our kinematic maps spatially registered onto the Hubble Space Telescope H$\alpha$ and Lyman $\alpha$ (Ly$\alpha$) images. Only for individual galaxies a causal connection between spatially resolved H$\alpha$ kinematics and Ly$\alpha$ photometry can be conjectured. However, no general trend can be established for the whole sample. Furthermore, we compute non-parametric global kinematical statistics -- intrinsic velocity dispersion $\sigma_0$, shearing velocity $v_\mathrm{shear}$, and the $v_\mathrm{shear}/\sigma_0$ ratio -- from our kinematic maps. In general LARS galaxies are characterised by high intrinsic velocity dispersions (54\,km\,s$^{-1}$ median) and low shearing velocities (65\,km\,s$^{-1}$ median). $v_\mathrm{shear}/\sigma_0$ values range from 0.5 to 3.2 with an average of 1.5. Noteworthy, five galaxies of the sample are dispersion dominated systems with $v_\mathrm{shear}/\sigma_0 <1$ and are thus kinematically similar to turbulent star forming galaxies seen at high redshift. When linking our kinematical statistics to the global LARS Ly$\alpha$ properties, we find that dispersion dominated systems show higher Ly$\alpha$ equivalent widths and higher Ly$\alpha$ escape fractions than systems with $v_\mathrm{shear}/\sigma_0 > 1$. Our result indicates that turbulence in actively star-forming systems is causally connected to interstellar medium conditions that favour an escape of Ly$\alpha$ radiation.Comment: 26 pages, 15 figures, accepted for publication in A&

Differentiation of human induced pluripotent stem cells into cortical neural stem cells

Efficient and effective methods for converting human induced pluripotent stem cells into differentiated derivatives are critical for performing robust, large-scale studies of development and disease modelling, and for providing a source of cells for regenerative medicine. Here, we describe a 14-day neural differentiation protocol which allows for the scalable, simultaneous differentiation of multiple iPSC lines into cortical neural stem cells We currently employ this protocol to differentiate and compare sets of engineered iPSC lines carrying loss of function alleles in developmental disorder associated genes, alongside isogenic wildtype controls. Using RNA sequencing (RNA-Seq), we can examine the changes in gene expression brought about by each disease gene knockout, to determine its impact on neural development and explore mechanisms of disease. The 10-day Neural Induction period uses the well established dual-SMAD inhibition approach combined with Wnt/beta-Catenin inhibition to selectively induce formation of cortical NSCs. This is followed by a 4-day Neural Maintenance period facilitating NSC expansion and rosette formation, and NSC cryopreservation. We also describe methods for thawing and passaging the cryopreserved NSCs, which are useful in confirming their viability for further culture. Routine implementation of immunocytochemistry Quality Control confirms the presence of PAX6-positive and/or FOXG1-positive NSCs and the absence of OCT4-positive iPSCs after differentiation. RNA-Seq, flow cytometry, immunocytochemistry (ICC) and RT-qPCR provide additional confirmation of robust presence of NSC markers in the differentiated cells. The broader utility and application of our protocol is demonstrated by the successful differentiation of wildtype iPSC lines from five additional independent donors. This paper thereby describes an efficient method for the production of large numbers of high purity cortical NSCs, which are widely applicable for downstream research into developmental mechanisms, further differentiation into postmitotic cortical neurons, or other applications such as large-scale drug screening experiments.Peer reviewe

The Role of Compensatory Beliefs in Rationalizing Environmentally Detrimental Behaviors

Compensatory green beliefs (CGBs) reflect the idea that a pro-environmental behavior (e.g., recycling) can off-set the negative effects of an environmentally detrimental behavior (e.g., driving). It is thought that CGBs might help explain why people act in ways that appear to contradict their pro-environmental intentions, and inconsistently engage in pro-environmental behaviors. The present study sought to investigate the nature and use of CGBs. A series of interviews suggested that participants endorsed CGBs to: (a) reduce feelings of guilt with respect to (the assumed or actual) negative environmental impact of their actions, and (b) to defend their green credentials in social situations. Participants also justified detrimental behaviors on the basis of higher loyalties (e.g., family’s needs), or the perceived difficulty of performing more pro-environmental actions. In addition to shedding light on how, when, and why people might hold and use CGBs, the research also provides new insight into how CGBs should be assessed

A diamond nanophotonic interface with an optically accessible deterministic electronuclear spin register

A contemporary challenge for the scalability of quantum networks is developing quantum nodes with simultaneous high photonic efficiency and long-lived qubits. Here, we present a fibre-packaged nanophotonic diamond waveguide hosting a tin-vacancy centre with a spin-1/2 $^{117}$Sn nucleus. The interaction between the electronic and nuclear spins results in a signature 452(7) MHz hyperfine splitting. This exceeds the natural optical linewidth by a factor of 16, enabling direct optical nuclear-spin initialisation with 98.6(3)% fidelity and single-shot readout with 80(1)% fidelity. The waveguide-to-fibre extraction efficiency of our device of 57(6)% enables the practical detection of 5-photon events. Combining the photonic performance with the optically initialised nuclear spin, we demonstrate a spin-gated single-photon nonlinearity with 11(1)% contrast in the absence of an external magnetic field. These capabilities position our nanophotonic interface as a versatile quantum node in the pursuit of scalable quantum networks

Composition of UHECR and the Pierre Auger Observatory Spectrum

We fit the recently published Pierre Auger ultra-high energy cosmic ray spectrum assuming that either nucleons or nuclei are emitted at the sources. We consider the simplified cases of pure proton, or pure oxygen, or pure iron injection. We perform an exhaustive scan in the source evolution factor, the spectral index, the maximum energy of the source spectrum Z E_{max}, and the minimum distance to the sources. We show that the Pierre Auger spectrum agrees with any of the source compositions we assumed. For iron, in particular, there are two distinct solutions with high and low E_{max} (e.g. 6.4 10^{20} eV and 2 10^{19} eV) respectively which could be distinguished by either a large fraction or the near absence of proton primaries at the highest energies. We raise the possibility that an iron dominated injected flux may be in line with the latest composition measurement from the Pierre Auger Observatory where a hint of heavy element dominance is seen.Comment: 19 pages, 6 figures (33 panels)- Uses iopart.cls and iopart12.clo- In version 2: addition of a few sentences and two reference

Hyperfine Spectroscopy of Isotopically Engineered Group-IV Color Centers in Diamond

A quantum register coupled to a spin-photon interface is a key component in quantum communication and information processing. Group-IV color centers in diamond (SiV, GeV, and SnV) are promising candidates for this application, comprising an electronic spin with optical transitions coupled to a nuclear spin as the quantum register. However, the creation of a quantum register for these color centers with deterministic and strong coupling to the spin-photon interface remains challenging. Here, we make first-principles predictions of the hyperfine parameters of the group-IV color centers, which we verify experimentally with a comprehensive comparison between the spectra of spin active and spin neutral intrinsic dopant nuclei in single GeV and SnV emitters. In line with the theoretical predictions, detailed spectroscopy on large sample sizes reveals that hyperfine coupling causes a splitting of the optical transition of SnV an order of magnitude larger than the optical linewidth and provides a magnetic-field insensitive transition. This strong coupling provides access to a new regime for quantum registers in diamond color centers, opening avenues for novel spin-photon entanglement and quantum sensing schemes for these well-studied emitters

Canvass: a crowd-sourced, natural-product screening library for exploring biological space

NCATS thanks Dingyin Tao for assistance with compound characterization. This research was supported by the Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (NIH). R.B.A. acknowledges support from NSF (CHE-1665145) and NIH (GM126221). M.K.B. acknowledges support from NIH (5R01GM110131). N.Z.B. thanks support from NIGMS, NIH (R01GM114061). J.K.C. acknowledges support from NSF (CHE-1665331). J.C. acknowledges support from the Fogarty International Center, NIH (TW009872). P.A.C. acknowledges support from the National Cancer Institute (NCI), NIH (R01 CA158275), and the NIH/National Institute of Aging (P01 AG012411). N.K.G. acknowledges support from NSF (CHE-1464898). B.C.G. thanks the support of NSF (RUI: 213569), the Camille and Henry Dreyfus Foundation, and the Arnold and Mabel Beckman Foundation. C.C.H. thanks the start-up funds from the Scripps Institution of Oceanography for support. J.N.J. acknowledges support from NIH (GM 063557, GM 084333). A.D.K. thanks the support from NCI, NIH (P01CA125066). D.G.I.K. acknowledges support from the National Center for Complementary and Integrative Health (1 R01 AT008088) and the Fogarty International Center, NIH (U01 TW00313), and gratefully acknowledges courtesies extended by the Government of Madagascar (Ministere des Eaux et Forets). O.K. thanks NIH (R01GM071779) for financial support. T.J.M. acknowledges support from NIH (GM116952). S.M. acknowledges support from NIH (DA045884-01, DA046487-01, AA026949-01), the Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program (W81XWH-17-1-0256), and NCI, NIH, through a Cancer Center Support Grant (P30 CA008748). K.N.M. thanks the California Department of Food and Agriculture Pierce's Disease and Glassy Winged Sharpshooter Board for support. B.T.M. thanks Michael Mullowney for his contribution in the isolation, elucidation, and submission of the compounds in this work. P.N. acknowledges support from NIH (R01 GM111476). L.E.O. acknowledges support from NIH (R01-HL25854, R01-GM30859, R0-1-NS-12389). L.E.B., J.K.S., and J.A.P. thank the NIH (R35 GM-118173, R24 GM-111625) for research support. F.R. thanks the American Lebanese Syrian Associated Charities (ALSAC) for financial support. I.S. thanks the University of Oklahoma Startup funds for support. J.T.S. acknowledges support from ACS PRF (53767-ND1) and NSF (CHE-1414298), and thanks Drs. Kellan N. Lamb and Michael J. Di Maso for their synthetic contribution. B.S. acknowledges support from NIH (CA78747, CA106150, GM114353, GM115575). W.S. acknowledges support from NIGMS, NIH (R15GM116032, P30 GM103450), and thanks the University of Arkansas for startup funds and the Arkansas Biosciences Institute (ABI) for seed money. C.R.J.S. acknowledges support from NIH (R01GM121656). D.S.T. thanks the support of NIH (T32 CA062948-Gudas) and PhRMA Foundation to A.L.V., NIH (P41 GM076267) to D.S.T., and CCSG NIH (P30 CA008748) to C.B. Thompson. R.E.T. acknowledges support from NIGMS, NIH (GM129465). R.J.T. thanks the American Cancer Society (RSG-12-253-01-CDD) and NSF (CHE1361173) for support. D.A.V. thanks the Camille and Henry Dreyfus Foundation, the National Science Foundation (CHE-0353662, CHE-1005253, and CHE-1725142), the Beckman Foundation, the Sherman Fairchild Foundation, the John Stauffer Charitable Trust, and the Christian Scholars Foundation for support. J.W. acknowledges support from the American Cancer Society through the Research Scholar Grant (RSG-13-011-01-CDD). W.M.W.acknowledges support from NIGMS, NIH (GM119426), and NSF (CHE1755698). A.Z. acknowledges support from NSF (CHE-1463819). (Intramural Research Program of the National Center for Advancing Translational Sciences, National Institutes of Health (NIH); CHE-1665145 - NSF; CHE-1665331 - NSF; CHE-1464898 - NSF; RUI: 213569 - NSF; CHE-1414298 - NSF; CHE1361173 - NSF; CHE1755698 - NSF; CHE-1463819 - NSF; GM126221 - NIH; 5R01GM110131 - NIH; GM 063557 - NIH; GM 084333 - NIH; R01GM071779 - NIH; GM116952 - NIH; DA045884-01 - NIH; DA046487-01 - NIH; AA026949-01 - NIH; R01 GM111476 - NIH; R01-HL25854 - NIH; R01-GM30859 - NIH; R0-1-NS-12389 - NIH; R35 GM-118173 - NIH; R24 GM-111625 - NIH; CA78747 - NIH; CA106150 - NIH; GM114353 - NIH; GM115575 - NIH; R01GM121656 - NIH; T32 CA062948-Gudas - NIH; P41 GM076267 - NIH; R01GM114061 - NIGMS, NIH; R15GM116032 - NIGMS, NIH; P30 GM103450 - NIGMS, NIH; GM129465 - NIGMS, NIH; GM119426 - NIGMS, NIH; TW009872 - Fogarty International Center, NIH; U01 TW00313 - Fogarty International Center, NIH; R01 CA158275 - National Cancer Institute (NCI), NIH; P01 AG012411 - NIH/National Institute of Aging; Camille and Henry Dreyfus Foundation; Arnold and Mabel Beckman Foundation; Scripps Institution of Oceanography; P01CA125066 - NCI, NIH; 1 R01 AT008088 - National Center for Complementary and Integrative Health; W81XWH-17-1-0256 - Office of the Assistant Secretary of Defense for Health Affairs through the Peer Reviewed Medical Research Program; P30 CA008748 - NCI, NIH, through a Cancer Center Support Grant; California Department of Food and Agriculture Pierce's Disease and Glassy Winged Sharpshooter Board; American Lebanese Syrian Associated Charities (ALSAC); University of Oklahoma Startup funds; 53767-ND1 - ACS PRF; PhRMA Foundation; P30 CA008748 - CCSG NIH; RSG-12-253-01-CDD - American Cancer Society; RSG-13-011-01-CDD - American Cancer Society; CHE-0353662 - National Science Foundation; CHE-1005253 - National Science Foundation; CHE-1725142 - National Science Foundation; Beckman Foundation; Sherman Fairchild Foundation; John Stauffer Charitable Trust; Christian Scholars Foundation)Published versionSupporting documentatio