Human Telomeres Are Tethered to the Nuclear Envelope during Postmitotic Nuclear Assembly

SummaryTelomeres are essential for nuclear organization in yeast and during meiosis in mice. Exploring telomere dynamics in living human cells by advanced time-lapse confocal microscopy allowed us to evaluate the spatial distribution of telomeres within the nuclear volume. We discovered an unambiguous enrichment of telomeres at the nuclear periphery during postmitotic nuclear assembly, whereas telomeres were localized more internally during the rest of the cell cycle. Telomere enrichment at the nuclear rim was mediated by physical tethering of telomeres to the nuclear envelope, most likely via specific interactions between the shelterin subunit RAP1 and the nuclear envelope protein Sun1. Genetic interference revealed a critical role in cell-cycle progression for Sun1 but no effect on telomere positioning for RAP1. Our results shed light on the dynamic relocalization of human telomeres during the cell cycle and suggest redundant pathways for tethering telomeres to the nuclear envelope

Supplementary data for the article: Fitzpatrick, A. J.; Stepanovic, S.; Müller-Bunz, H.; Gruden-Pavlović, M. A.; García-Fernández, P.; Morgan, G. G. Challenges in Assignment of Orbital Populations in a High Spin Manganese(Iii) Complex. Dalton Transactions 2016, 45 (15), 6702–6708. https://doi.org/10.1039/c5dt03914b

Supplementary material for: [https://doi.org/10.1039/c5dt03914b]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1912]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/3395

Cryo-EM structures of tau filaments from Alzheimer's disease

Alzheimer's disease is the most common neurodegenerative disease, and there are no mechanism-based therapies. The disease is defined by the presence of abundant neurofibrillary lesions and neuritic plaques in the cerebral cortex. Neurofibrillary lesions comprise paired helical and straight tau filaments, whereas tau filaments with different morphologies characterize other neurodegenerative diseases. No high-resolution structures of tau filaments are available. Here we present cryo-electron microscopy (cryo-EM) maps at 3.4-3.5 Å resolution and corresponding atomic models of paired helical and straight filaments from the brain of an individual with Alzheimer's disease. Filament cores are made of two identical protofilaments comprising residues 306-378 of tau protein, which adopt a combined cross-β/β-helix structure and define the seed for tau aggregation. Paired helical and straight filaments differ in their inter-protofilament packing, showing that they are ultrastructural polymorphs. These findings demonstrate that cryo-EM allows atomic characterization of amyloid filaments from patient-derived material, and pave the way for investigation of a range of neurodegenerative diseases

Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods

Background: Short-chain fatty acids (SCFAs), metabolites produced through the microbial fermentation of nondigestible dietary components, have key roles in energy homeostasis. Animal research suggests that colon-derived SCFAs modulate feeding behavior via central mechanisms. In humans, increased colonic production of the SCFA propionate acutely reduces energy intake. However, evidence of an effect of colonic propionate on the human brain or reward-based eating behavior is currently unavailable. Objectives: We investigated the effect of increased colonic propionate production on brain anticipatory reward responses during food picture evaluation. We hypothesized that elevated colonic propionate would reduce both reward responses and ad libitum energy intake via stimulation of anorexigenic gut hormone secretion. Design: In a randomized crossover design, 20 healthy nonobese men completed a functional magnetic resonance imaging (fMRI) food picture evaluation task after consumption of control inulin or inulin-propionate ester, a unique dietary compound that selectively augments colonic propionate production. The blood oxygen level–dependent (BOLD) signal was measured in a priori brain regions involved in reward processing, including the caudate, nucleus accumbens, amygdala, anterior insula, and orbitofrontal cortex (n = 18 had analyzable fMRI data). Results: Increasing colonic propionate production reduced BOLD signal during food picture evaluation in the caudate and nucleus accumbens. In the caudate, the reduction in BOLD signal was driven specifically by a lowering of the response to high-energy food. These central effects were partnered with a decrease in subjective appeal of high-energy food pictures and reduced energy intake during an ad libitum meal. These observations were not related to changes in blood peptide YY (PYY), glucagon-like peptide 1 (GLP-1), glucose, or insulin concentrations. Conclusion: Our results suggest that colonic propionate production may play an important role in attenuating reward-based eating behavior via striatal pathways, independent of changes in plasma PYY and GLP-1. This trial was registered at clinicaltrials.gov as NCT00750438

4D Cryo-Electron Microscopy of Proteins

Cryo-electron microscopy is a form of transmission electron microscopy that has been used to determine the 3D structure of biological specimens in the hydrated state and with high resolution. We report the development of 4D cryo-electron microscopy by integrating the fourth dimension, time, into this powerful technique. From time-resolved diffraction of amyloid fibrils in a thin layer of vitrified water at cryogenic temperatures, we were able to detect picometer movements of protein molecules on a nanosecond time scale. Potential future applications of 4D cryo-electron microscopy are numerous, and some are discussed here

UV Absorption Lines from High-Velocity Gas in the Vela Supernova Remnant: New insights from STIS Echelle Observations of HD72089

The star HD72089 is located behind the Vela supernova remnant and shows a complex array of high and low velocity interstellar absorption features arising from shocked clouds. A spectrum of this star was recorded over the wavelength range 1196.4 to 1397.2 Angstroms at a resolving power lambda/Delta lambda = 110,000 and signal-to-noise ratio of 32 by STIS on the Hubble Space Telescope. We have identified 7 narrow components of C I and have measured their relative populations in excited fine-structure levels. Broader features at heliocentric velocities ranging from -70 to +130 km/s are seen in C II, N I, O I, Si II, S II and Ni II. In the high-velocity components, the unusually low abundances of N I and O I, relative to S II and Si II, suggest that these elements may be preferentially ionized to higher stages by radiation from hot gas immediately behind the shock fronts.Comment: 11 pages, 2 figures, Latex. Submitted for the special HST ERO issue of the Astrophysical Journal Letter

Challenges in assignment of orbital populations in a high spin manganese(III) complex

Magnetic, structural and computational data of four complex salts with the same mononuclear high spin octahedral Mn(III) complex cation are reported. The manifestation of Jahn-Teller-like distortions in the Mn(III) cation is dependent on the nature of the charge-balancing anion, with small anions yielding a planar elongation and large anions freezing out a preferential axial elongation along one of the amine-Mn-imine directions within that same plane. Modulation of the lattice by changing the charge balancing anion results in mixing of the orbital symmetry due to vibrational perturbation.This is peer-reviewed version of the following article: Fitzpatrick, A. J.; Stepanovic, S.; Müller-Bunz, H.; Gruden-Pavlović, M. A.; García-Fernández, P.; Morgan, G. G. Challenges in Assignment of Orbital Populations in a High Spin Manganese(Iii) Complex. Dalton Transactions 2016, 45 (15), 6702–6708. [https://doi.org/10.1039/c5dt03914b]Supplementary material: [http://cherry.chem.bg.ac.rs/handle/123456789/3396

Supplementary data for the article: Fitzpatrick, A. J.; Stepanovic, S.; Müller-Bunz, H.; Gruden-Pavlović, M. A.; García-Fernández, P.; Morgan, G. G. Challenges in Assignment of Orbital Populations in a High Spin Manganese(Iii) Complex. Dalton Transactions 2016, 45 (15), 6702–6708. https://doi.org/10.1039/c5dt03914b

Supplementary material for: [https://doi.org/10.1039/c5dt03914b]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1912]Related to accepted version: [http://cherry.chem.bg.ac.rs/handle/123456789/3395

Metastability of native proteins and the phenomenon of amyloid formation

An experimental determination of the thermodynamic stabilities of a series of amyloid fibrils reveals that this structural form is likely to be the most stable one that protein molecules can adopt even under physiological conditions. This result challenges the conventional assumption that functional forms of proteins correspond to the global minima in their free energy surfaces and suggests that living systems are conformationally as well as chemically metastable. © 2011 American Chemical Society