Structure and stereochemistry of the base excision repair glycosylase MutY reveal a mechanism similar to retaining glycosidases.

MutY adenine glycosylases prevent DNA mutations by excising adenine from promutagenic 8-oxo-7,8-dihydroguanine (OG):A mismatches. Here, we describe structural features of the MutY active site bound to an azaribose transition state analog which indicate a catalytic role for Tyr126 and approach of the water nucleophile on the same side as the departing adenine base. The idea that Tyr126 participates in catalysis, recently predicted by modeling calculations, is strongly supported by mutagenesis and by seeing close contact between the hydroxyl group of this residue and the azaribose moiety of the transition state analog. NMR analysis of MutY methanolysis products corroborates a mechanism for adenine removal with retention of stereochemistry. Based on these results, we propose a revised mechanism for MutY that involves two nucleophilic displacement steps akin to the mechanisms accepted for 'retaining' O-glycosidases. This new-for-MutY yet familiar mechanism may also be operative in related base excision repair glycosylases and provides a critical framework for analysis of human MutY (MUTYH) variants associated with inherited colorectal cancer

Erratum: “Seed layer technique for high quality epitaxial manganite films” [AIP Advances 6, 085109 (2016)]

No abstract available

Turbulent Mixing in the Interstellar Medium -- an application for Lagrangian Tracer Particles

We use 3-dimensional numerical simulations of self-gravitating compressible turbulent gas in combination with Lagrangian tracer particles to investigate the mixing process of molecular hydrogen (H2) in interstellar clouds. Tracer particles are used to represent shock-compressed dense gas, which is associated with H2. We deposit tracer particles in regions of density contrast in excess of ten times the mean density. Following their trajectories and using probability distribution functions, we find an upper limit for the mixing timescale of H2, which is of order 0.3 Myr. This is significantly smaller than the lifetime of molecular clouds, which demonstrates the importance of the turbulent mixing of H2 as a preliminary stage to star formation.Comment: 10 pages, 5 figures, conference proceedings "Turbulent Mixing and Beyond 2007

Palliative care interventions in advanced dementia

BACKGROUND: Dementia is a chronic, progressive and ultimately fatal neurodegenerative disease. Advanced dementia is characterised by profound cognitive impairment, inability to communicate verbally and complete functional dependence. Usual care of people with advanced dementia is not underpinned universally by a palliative approach. Palliative care has focused traditionally on care of people with cancer, but for more than a decade, there have been calls worldwide to extend palliative care services to include all people with life-limiting illnesses in need of specialist care, including people with dementia. This review is an updated version of a review first published in 2016. OBJECTIVES: To assess the effect of palliative care interventions in advanced dementia. SEARCH METHODS: We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group's Specialised Register on 7 October 2020. ALOIS contains records of clinical trials identified from monthly searches of several major healthcare databases, trial registries and grey literature sources. We ran additional searches across MEDLINE (OvidSP), Embase (OvidSP), four other databases and two trial registries on 7 October 2020 to ensure that the searches were as comprehensive and as up-to-date as possible. SELECTION CRITERIA: We searched for randomised (RCTs) and non-randomised controlled trials (nRCTs), controlled before-and-after studies and interrupted time series studies evaluating the impact of palliative care interventions for adults with advanced dementia of any type. Participants could be people with advanced dementia, their family members, clinicians or paid care staff. We included clinical interventions and non-clinical interventions. Comparators were usual care or another palliative care intervention. We did not exclude studies based on outcomes measured. DATA COLLECTION AND ANALYSIS: At least two review authors (SW, EM, PC) independently assessed all potential studies identified in the search against the review inclusion criteria. Two authors independently extracted data from eligible studies. Where appropriate, we estimated pooled treatment effects in a fixed-effect meta-analysis. We assessed the risk of bias of included studies using the Cochrane Risk of Bias tool and the overall certainty of the evidence for each outcome using GRADE. MAIN RESULTS: Nine studies (2122 participants) met the review inclusion criteria. Two studies were individually-randomised RCTs, six were cluster-randomised RCTs and one was a controlled before-and-after study. We conducted two separate comparisons: organisation and delivery of care interventions versus usual care (six studies, 1162 participants) and advance care planning interventions versus usual care (three studies, 960 participants). Two studies were carried out in acute hospitals and seven in nursing homes or long-term care facilities. For both comparisons, we found the included studies to be sufficiently similar to conduct meta-analyses. Changes to the organisation and delivery of care for people with advanced dementia may increase comfort in dying (MD 1.49, 95% CI 0.34 to 2.64; 5 studies, 335 participants; very low certainty evidence). However, the evidence is very uncertain and unlikely to be clinically significant. These changes may also increase the likelihood of having a palliative care plan in place (RR 5.84, 95% CI 1.37 to 25.02; 1 study, 99 participants; I2 = 0%; very low certainty evidence), but again the evidence is very uncertain. Such interventions probably have little effect on the use of non-palliative interventions (RR 1.11, 95% CI 0.71 to 1.72; 2 studies, 292 participants; I2 = 0%; moderate certainty evidence). They may also have little or no effect on documentation of advance directives (RR 1.46, 95% CI 0.50 to 4.25; 2 studies, 112 participants; I2 = 52%; very low certainty evidence), or whether discussions take place about advance care planning (RR 1.08, 95% CI 1.00 to 1.18; 1 study, 193 participants; I2 = 0%; very low certainty evidence) and goals of care (RR 2.36, 95% CI 1.00 to 5.54; 1 study, 13 participants; I2 = 0%; low certainty evidence). No included studies assessed adverse effects. Advance care planning interventions for people with advanced dementia probably increase the documentation of advance directives (RR 1.23, 95% CI 1.07 to 1.41; 2 studies, 384; moderate certainty evidence) and the number of discussions about goals of care (RR 1.33, 95% CI 1.11 to 1.59; 2 studies, 384 participants; moderate certainty evidence). They may also slightly increase concordance with goals of care (RR 1.39, 95% CI 1.08 to 1.79; 1 study, 63 participants; low certainty evidence). On the other hand, they may have little or no effect on perceived symptom management (MD -1.80, 95% CI -6.49 to 2.89; 1 study, 67 participants; very low certainty evidence) or whether advance care planning discussions occur (RR 1.04, 95% CI 0.87 to 1.24; 1 study, 67 participants; low certainty evidence). AUTHORS' CONCLUSIONS: The evidence on palliative care interventions in advanced dementia is limited in quantity and certainty. When compared to usual care, changes to the organisation and delivery of care for people with advanced dementia may lead to improvements in comfort in dying, but the evidence for this was of very low certainty. Advance care planning interventions, compared to usual care, probably increase the documentation of advance directives and the occurrence of discussions about goals of care, and may also increase concordance with goals of care. We did not detect other effects. The uncertainty in the evidence across all outcomes in both comparisons is mainly driven by imprecision of effect estimates and risk of bias in the included studies

Descendants of the first stars: the distinct chemical signature of second generation stars

Extremely metal-poor (EMP) stars in the Milky Way (MW) allow us to infer the properties of their progenitors by comparing their chemical composition to the metal yields of the first supernovae. This method is most powerful when applied to mono-enriched stars, i.e. stars that formed from gas that was enriched by only one previous supernova. We present a novel diagnostic to identify this subclass of EMP stars. We model the first generations of star formation semi-analytically, based on dark matter halo merger trees that yield MW-like halos at the present day. Radiative and chemical feedback are included self-consistently and we trace all elements up to zinc. Mono-enriched stars account for only $\sim 1\%$ of second generation stars in our fiducial model and we provide an analytical formula for this probability. We also present a novel analytical diagnostic to identify mono-enriched stars, based on the metal yields of the first supernovae. This new diagnostic allows us to derive our main results independently from the specific assumptions made regarding Pop III star formation, and we apply it to a set of observed EMP stars to demonstrate its strengths and limitations. Our results may provide selection criteria for current and future surveys and therefore contribute to a deeper understanding of EMP stars and their progenitors.Comment: 18 pages, 20 figures, published in MNRA

Digital direct electron imaging of energy-filtered electron backscatter diffraction patterns

Electron backscatter diffraction is a scanning electron microscopy technique used to obtain crystallographic information on materials. It allows the nondestructive mapping of crystal structure, texture, and strain with a lateral and depth resolution on the order of tens of nanometers. Electron backscatter diffraction patterns (EBSPs) are presently acquired using a detector comprising a scintillator coupled to a digital camera, and the crystallographic information obtainable is limited by the conversion of electrons to photons and then back to electrons again. In this article we will report the direct acquisition of energy-filtered EBSPs using a digital complementary metal-oxide-semiconductor hybrid pixel detector, Timepix. We show results from a range of samples with different mass and density, namely diamond, silicon, and GaN. Direct electron detection allows the acquisition of EBSPs at lower (≤5 keV) electron beam energies. This results in a reduction in the depth and lateral extension of the volume of the specimen contributing to the pattern and will lead to a significant improvement in lateral and depth resolution. Direct electron detection together with energy filtering (electrons having energy below a specific value are excluded) also leads to an improvement in spatial resolution but in addition provides an unprecedented increase in the detail in the acquired EBSPs. An increase in contrast and higher-order diffraction features are observed. In addition, excess-deficiency effects appear to be suppressed on energy filtering. This allows the fundamental physics of pattern formation to be interrogated and will enable a change in the use of electron backscatter diffraction (EBSD) for crystal phase identification and the mapping of strain. The enhancement in the contrast in high-pass energy-filtered EBSD patterns is found to be stronger for lighter, less dense materials. The improved contrast for such materials will enable the application of the EBSD technique to be expanded to materials for which conventional EBSD analysis is not presently practicable

Diffractive triangulation of radiative point sources

We describe a general method to determine the location of a point source of waves relative to a twodimensional single-crystalline active pixel detector. Based on the inherent structural sensitivity of crystalline sensor materials, characteristic detector diffraction patterns can be used to triangulate the location of a wave emitter. The principle described here can be applied to various types of waves, provided that the detector elements are suitably structured. As a prototypical practical application of the general detection principle, a digital hybrid pixel detector is used to localize a source of electrons for Kikuchi diffraction pattern measurements in the scanning electron microscope. This approach provides a promising alternative method to calibrate Kikuchi patterns for accurate measurements of microstructural crystal orientations, strains, and phase distributions

Spatially Controlled Generation and Probing of Random Telegraph Noise in Metal Nanocrystal Embedded HfO2Using Defect Nanospectroscopy

Random telegraph noise (RTN) is often considered a nuisance or, more critically, a key reliability challenge for miniaturized semiconductor devices. However, this picture is gradually changing as recent works have shown emerging applications based on the inherent randomness of the RTN signals in state-of-The-Art technologies, including true random number generator and IoT hardware security. Suitable material platforms and device architectures are now actively explored to bring these technologies from an embryonic stage to practical application. A key challenge is to devise material systems, which can be reliably used for the deterministic creation of localized defects to be used for RTN generation. Toward this goal, we have investigated RTN in Au nanocrystal (Au-NC) embedded HfO2stacks at the nanoscale by combining conduction atomic force microscopy defect spectroscopy and a statistical factorial hidden Markov model analysis. With a voltage applied across the stack, there is an enhanced asymmetric electric field surrounding the Au-NC. This in turn leads to the preferential generation of atomic defects in the HfO2near the Au-NC when voltage is applied to the stack to induce dielectric breakdown. Since RTN arises from various electrostatic interactions between closely spaced atomic defects, the Au-NC HfO2material system exhibits an intrinsic ability to generate RTN signals. Our results also highlight that the spatial confinement of multiple defects and the resulting electrostatic interactions between the defects provides a dynamic environment leading to many complex RTN patterns in addition to the presence of the standard two-level RTN signals. The insights obtained at the nanoscale are useful to optimize metal nanocrystal embedded high-κ stacks and circuits for on-demand generation of RTN for emerging random number applications