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The Rad50‐Mre11 nuclease complex plays a vital role in DNA repair in all domains of life. It recognizes and processes DNA double‐strand breaks. Rad50 proteins fold into an extended structure with a 20 to 60 nm long coiled coil connecting a globular ABC ATPase domain with a zinc hook dimerization domain. A published structure of an archaeal Rad50 zinc hook shows coiled coils pointing away from each other. Here we present the crystal structure of an alternate conformation displaying co‐aligned coiled coils. Archaeal Rad50 may thus switch between rod‐shaped and ring‐like conformations as recently proposed for a bacterial homolog. [ABSTRACT FROM AUTHOR]

Correct bioriented attachment of sister chromatids to the mitotic spindle is essential for chromosome segregation. In budding yeast, the conserved protein shugoshin (Sgo1) contributes to biorientation by recruiting the protein phosphatase PP2A-Rts1 and the condensin complex to centromeres. Using peptide prints, we identified a Serine-Rich Motif (SRM) of Sgo1 that mediates the interaction with condensin and is essential for centromeric condensin recruitment and the establishment of biorientation. We show that the interaction is regulated via phosphorylation within the SRM and we determined the phospho-sites using mass spectrometry. Analysis of the phosphomimic and phosphoresistant mutants revealed that SRM phosphorylation disrupts the shugoshin–condensin interaction. We present evidence that Mps1, a central kinase in the spindle assembly checkpoint, directly phosphorylates Sgo1 within the SRM to regulate the interaction with condensin and thereby condensin localization to centromeres. Our findings identify novel mechanisms that control shugoshin activity at the centromere in budding yeast. Author summary: Proper chromosome segregation in eukaryotes is ensured through correct attachment of the spindle microtubules to the centromeric chromosomal regions. The attachment is mediated via the multimolecular proteinaceous complex called the kinetochore. This enables the establishment of bioirentation, when each sister chromatid is attached to microtubules emanating from opposite spindle poles. Shugoshin (Sgo1) is a conserved centromeric protein that facilitates biorientation through its interactions with the protein phosphatase PP2A/Rts1, chromosome passenger complex and centromeric condensin. Here, we identified a serine-rich motif that is required for the interaction of shugoshin with the condensin complex. We show that loss of this region impairs condensin enrichment at the centromere, chromosome biorientation, segregation as well as the function of the chromosome passenger complex in the error correction. Moreover, the interaction is phosphoregulated, as phosphorylation of the serine-rich motif on Sgo1 disrupts its interaction with condensin. Finally, we show that the conserved spindle assembly checkpoint kinase Mps1 is responsible for this phosphorylation. Our findings uncover novel regulatory mechanisms that facilitate proper chromosome segregation. [ABSTRACT FROM AUTHOR]

Purpose: A properly characterized macromolecular (MM) contribution is essential for accurate metabolite quantification in FID‐MRSI. MM information can be included into the fitting model as a single component or parameterized and included over several individual MM resonances, which adds flexibility when pathologic changes are present but is prone to potential overfitting. This study investigates the effects of different MM models on MRSI reproducibility. Methods: Clinically feasible, high‐resolution FID‐MRSI data were collected in ~5 min at 7 Tesla from 10 healthy volunteers and quantified via LCModel (version 6.3) with 3 basis sets, each with a different approach for how the MM signal was handled: averaged measured whole spectrum (full MM), 9 parameterized components (param MM) with soft constraints to avoid overparameterization, or without any MM information included in the fitting prior knowledge. The test–retest reproducibility of MRSI scans was assessed voxel‐wise using metabolite coefficients of variation and intraclass correlation coefficients and compared between the basis sets. Correlations of concentration estimates were investigated for the param MM fitting model. Results: The full MM model provided the most reproducible quantification of total NAA, total Cho, myo‐inositol, and glutamate + glutamine ratios to total Cr (coefficients of variations ≤ 8%, intraclass correlation coefficients ≥ 0.76). Using the param MM model resulted in slightly lower reproducibility (up to +3% higher coefficients of variations, up to −0.1 decreased intraclass correlation coefficients). The quantification of the parameterized macromolecules did not affect quantification of the overlapping metabolites. Conclusion: Clinically feasible FID‐MRSI with an experimentally acquired MM spectrum included in prior knowledge provides highly reproducible quantification for the most common neurometabolites in healthy volunteers. Parameterization of the MM spectrum may be preferred as a compromise between quantification accuracy and reproducibility when the MM content is expected to be pathologically altered. [ABSTRACT FROM AUTHOR]

Research points out that cohesin holds sister DNAs within a single ring and that all SMC protein complexes, like cohesin, allow passage of DNA inside two arms held together by Scc1-like bridges that open and close. This mechanism regulate the DNA packing within cells.

Purpose: To assess the performance, in the presence of scanner instabilities, of three dynamic correction methods which integrate ∆B0 mapping into the chemical exchange saturation transfer (CEST) measurement and three established static ∆B0‐correction approaches. Methods: A homogeneous phantom and five healthy volunteers were scanned with a CEST sequence at 7 T. The in vivo measurements were performed twice: first with unaltered system frequency and again applying frequency shifts during the CEST acquisition. In all cases, retrospective voxel‐wise ∆B0‐correction was performed using one intrinsic and two extrinsic [prescans with dual‐echo gradient‐echo and water saturation shift referencing (WASSR)] static approaches. These were compared with two intrinsic [using phase data directly generated by single‐echo or double‐echo GRE (gradient‐echo) CEST readout (CEST‐GRE‐2TE)] and one extrinsic [phase from interleaved dual‐echo EPI (echo planar imaging) navigator (NAV‐EPI‐2TE)] dynamic ∆B0‐correction approaches [allowing correction of each Z‐spectral point before magnetization transfer ratio asymmetry (MTRasym) analysis]. Results: All three dynamic methods successfully mapped the induced drift. The intrinsic approaches were affected by the CEST labeling near water (∆ω < |0.3| ppm). The MTRasym contrast was distorted by the frequency drift in the brain by up to 0.21%/Hz when static ∆B0‐corrections were applied, whereas the dynamic ∆B0 corrections reduced this to <0.01%/Hz without the need of external scans. The CEST‐GRE‐2TE and NAV‐EPI‐2TE resulted in highly consistent MTRasym values with/without drift for all subjects. Conclusion: Reliable correction of scanner instabilities is essential to establish clinical CEST MRI. The three dynamic approaches presented improved the ∆B0‐correction performance significantly in the presence of frequency drift compared to established static methods. Among them, the self‐corrected CEST‐GRE‐2TE was the most accurate and straightforward to implement. [ABSTRACT FROM AUTHOR]

Purpose: Inhomogeneities in the static magnetic field (B0) deteriorate MRSI data quality by lowering the spectral resolution and SNR. MRSI with low spatial resolution is also prone to lipid bleeding. These problems are increasingly problematic at ultra‐high fields. An approach to tackling these challenges independent of B0‐shim hardware is to increase the spatial resolution. Therefore, we investigated the effect of improved spatial resolution on spectral quality and quantification at 4 field strengths. Methods: Whole‐brain MRSI data was simulated for 3 spatial resolutions and 4 B0s based on experimentally acquired MRI data and simulated free induction decay signals of metabolites and lipids. To compare the spectral quality and quantification, we derived SNR normalized to the voxel size (nSNR), linewidth and metabolite concentration ratios, their Cramer‐Rao‐lower‐bounds (CRLBs), and the absolute percentage error (APE) of estimated concentrations compared to the gold standard for the whole‐brain and 8 brain regions. Results: At 7T, we found up to a 3.4‐fold improved nSNR (in the frontal lobe) and a 2.8‐fold reduced linewidth (in the temporal lobe) for 1 cm3 versus 0.25 cm3 resolution. This effect was much more pronounced at higher and less homogenous B0 (1.6‐fold improved nSNR and 1.8‐fold improved linewidth in the parietal lobe at 3T). This had direct implications for quantification: the volume of reliably quantified spectra increased with resolution by 1.2‐fold and 1.5‐fold (when thresholded by CRLBs or APE, respectively). Conclusion: MRSI data quality benefits from increased spatial resolution particularly at higher B0, and leads to more reliable metabolite quantification. In conjunction with the development of better B0 shimming hardware, this will enable robust whole‐brain MRSI at ultra‐high field. [ABSTRACT FROM AUTHOR]

Proton MRS (1H MRS) provides noninvasive, quantitative metabolite profiles of tissue and has been shown to aid the clinical management of several brain diseases. Although most modern clinical MR scanners support MRS capabilities, routine use is largely restricted to specialized centers with good access to MR research support. Widespread adoption has been slow for several reasons, and technical challenges toward obtaining reliable good‐quality results have been identified as a contributing factor. Considerable progress has been made by the research community to address many of these challenges, and in this paper a consensus is presented on deficiencies in widely available MRS methodology and validated improvements that are currently in routine use at several clinical research institutions. In particular, the localization error for the PRESS localization sequence was found to be unacceptably high at 3 T, and use of the semi‐adiabatic localization by adiabatic selective refocusing sequence is a recommended solution. Incorporation of simulated metabolite basis sets into analysis routines is recommended for reliably capturing the full spectral detail available from short TE acquisitions. In addition, the importance of achieving a highly homogenous static magnetic field (B0) in the acquisition region is emphasized, and the limitations of current methods and hardware are discussed. Most recommendations require only software improvements, greatly enhancing the capabilities of clinical MRS on existing hardware. Implementation of these recommendations should strengthen current clinical applications and advance progress toward developing and validating new MRS biomarkers for clinical use. [ABSTRACT FROM AUTHOR]

Simulations of land-surface processes and phenomena often require driving time series of meteorological variables. Corresponding observations, however, are unavailable in most locations, even more so, when considering the duration, continuity and data quality required. Atmospheric reanalyses provide global coverage of relevant meteorological variables, but their use is largely restricted to grid-based studies. This is because technical challenges limit the ease with which reanalysis data can be applied to models at the site scale. We present the software toolkit GlobSim, which automates the downloading, interpolation and scaling of different reanalyses - currently ERA-5, ERA-Interim, JRA-55 and MERRA-2 - to produce meteorological time series for user-defined point locations. The resulting data have consistent structure and units to efficiently support ensemble simulation. The utility of GlobSim is demonstrated using an application in permafrost research. We perform ensemble simulations of ground-surface temperature for ten terrain types in a remote tundra area in northern Canada and compare the results with observations. Simulation results reproduced seasonal cycles and variation between terrain types well, demonstrating that GlobSim can support efficient land-surface simulations. Ensemble means often yielded better accuracy than individual simulation and ensemble ranges additionally provide indications of uncertainty arising from uncertain input. By improving the usability of reanalyses for research requiring time-series of climate variables for point locations, GlobSim can enable a wide range of simulation studies and model evaluations that previously were impeded by technical hurdles in obtaining suitable data. [ABSTRACT FROM AUTHOR]

The Canadian Land Surface Scheme and Canadian Terrestrial Ecosystem Model (CLASS-CTEM) together form the land surface component of the Canadian Earth System model (CanESM). Here we investigate the impact of changes to CLASS-CTEM that are designed to improve the simulation of permafrost physics. Eighteen tests were performed including changing the model configuration (number and depth of ground layers, different soil permeable depth datasets, adding a surface moss layer), and investigating alternative parameterizations of soil hydrology, soil thermal conductivity and snow properties. To evaluate these changes, outputs from CLASS-CTEM were compared to 1570 active layer thickness (ALT) measurements from 97 observation sites that are part of the Global Terrestrial Network for Permafrost (GTN-P), 105 106 monthly ground temperature observations from 132 GTN-P borehole sites, a blend of 5 observation-based snow water equivalent (SWE) datasets (Blended-5), remotely-sensed albedo, and seasonal discharge for major rivers draining permafrost regions. From the tests performed, the final revised model configuration has more ground layers (increased from 3 to 20) extending to greater depth (from 4.1m to 61.4m) and uses a new soil permeable depths dataset with a surface layer of moss added. The most beneficial change to the model parameterizations was incorporation of unfrozen water in frozen soils. These changes to CLASS-CTEM cause a small improvement in simulated SWE with little change in surface albedo but greatly improve the model performance at the GTN-P ALT and borehole sites. Compared to the GTN-P observations, the revised CLASS-CTEM ALTs have a weighted mean absolute error (wMAE) of 0.41-0.47m (depending on configuration), improved from >2.5m for the original model, while the borehole sites see a consistent improvement in wMAE for most seasons and depths considered, with seasonal wMAE values for the shallow surface layers of the revised model simulation at most 1.2°C greater than those calculated for the model driving screen-level air temperature compared to observations at the sites. Sub-grid heterogeneity estimates were derived from the standard deviation of ALT on the 1km² measurement grids at the GTN-P ALT sites, the spread in wMAE in grid cells with multiple GTN-P ALT sites, as well as from 35 boreholes measured within a 1200km² region as part of the Slave Province Surficial Materials and Permafrost Study. Given the size of the model grid cells (ca. 2.8°), sub-grid heterogeneity makes it likely difficult to appreciably reduce the wMAE of ALT or borehole temperatures much further. [ABSTRACT FROM AUTHOR]

Rockfalls and rock avalanches are a recurrent process in high mountain areas like the Mont Blanc massif. These processes are surveyed due to the hazard they present for infrastructure and alpinists. While rockfalls and rock avalanches have been documented for the last 150 years, we know very little about their frequency since the Last Glacial Maximum (LGM). In order to improve our understanding, it is imperative to date them on a longer timescale. A pilot campaign using Terrestrial Cosmogenic Nuclide (TCN) dating of five samples was carried out in 2006 at the Aiguille du Midi (3842 m a.s.l.). In 2011, a larger scale study (20 samples) was carried out in five other test sites in the Mont Blanc massif. This paper presents the exposure ages of the 2011 TCN study as well as the updated exposure ages of the 2006 study using newer TCN dating parameters. Most of these exposure ages lie within the Holocene but three ages are Pleistocene (59.87 ± 6.10 ka for the oldest). A comparison of these ages with air temperature and glacier cover proxies explored the possible relationship between the most active rockfall periods and the warmest periods of the Holocene: two clusters of exposure ages have been detected, corresponding to the Middle Holocene (8.2-4.2 ka) and the Roman Warm Period (c. 2 ka) climate periods. Some recent rockfalls have also been dated (< 0.56 ka). [ABSTRACT FROM AUTHOR]

Bacterial cells require DNA segregation machinery to properly distribute a genome to both daughter cells upon division. The most common system involved in chromosome and plasmid segregation in bacteria is the ParABS system. A core protein of this system - partition protein B (ParB) - regulates chromosome organization and chromosome segregation during the bacterial cell cycle. Over the past decades, research has greatly advanced our knowledge of the ParABS system. However, many intricate details of the mechanism of ParB proteins were only recently uncovered using in vitro single-molecule techniques. These approaches allowed the exploration of ParB proteins in precisely controlled environments, free from the complexities of the cellular milieu. This review covers the early developments of this field but emphasizes recent advances in our knowledge of the mechanistic understanding of ParB proteins as revealed by in vitro single-molecule methods. Furthermore, we provide an outlook on future endeavors in investigating ParB, ParB-like proteins, and their interaction partners. [ABSTRACT FROM AUTHOR]