The C-terminus of p63 contains multiple regulatory elements with different functions

The transcription factor p63 is expressed as at least six different isoforms, of which two have been assigned critical biological roles within ectodermal development and skin stem cell biology on the one hand and supervision of the genetic stability of oocytes on the other hand. These two isoforms contain a C-terminal inhibitory domain that negatively regulates their transcriptional activity. This inhibitory domain contains two individual components: one that uses an internal binding mechanism to interact with and mask the transactivation domain and one that is based on sumoylation. We have carried out an extensive alanine scanning study to identify critical regions within the inhibitory domain. These experiments show that a stretch of ~13 amino acids is crucial for the binding function. Further, investigation of transcriptional activity and the intracellular level of mutants that cannot be sumoylated suggests that sumoylation reduces the concentration of p63. We therefore propose that the inhibitory function of the C-terminal domain is in part due to direct inhibition of the transcriptional activity of the protein and in part due to indirect inhibition by controlling the concentration of p63. Keywords: p63, transcriptional regulation, auto-inhibition, sumoylatio

Theories of Low-Energy Quasi-Particle States in Disordered d-Wave Superconductors

The physics of low-energy quasi-particle excitations in disordered d-wave superconductors is a subject of ongoing intensive research. Over the last decade, a variety of conceptually and methodologically different approaches to the problem have been developed. Unfortunately, many of these theories contradict each other, and the current literature displays a lack of consensus on even the most basic physical observables. Adopting a symmetry-oriented approach, the present paper attempts to identify the origin of the disagreement between various previous approaches, and to develop a coherent theoretical description of the different low-energy regimes realized in weakly disordered d-wave superconductors. We show that, depending on the presence or absence of time-reversal invariance and the microscopic nature of the impurities, the system falls into one of four different symmetry classes. By employing a field-theoretical formalism, we derive effective descriptions of these universal regimes as descendants of a common parent field theory of Wess-Zumino-Novikov-Witten type. As well as describing the properties of each universal regime, we analyse a number of physically relevant crossover scenarios, and discuss reasons for the disagreement between previous results. We also touch upon other aspects of the phenomenology of the d-wave superconductor such as quasi-particle localization properties, the spin quantum Hall effect, and the quasi-particle physics of the disordered vortex lattice.Comment: 42 Pages, 8 postscript figures, published version with updated reference

Spectral and Transport Properties of d-Wave Superconductors With Strong Impurities

One of the remarkable features of disordered d-wave superconductors is strong sensitivity of long range properties to the microscopic realization of the disorder potential. Particularly rich phenomenology is observed for the -- experimentally relevant -- case of dilute distributions of isolated impurity centers. Building on earlier diagrammatic analyses, the present paper derives and analyses a low energy effective field theory of this system. Specifically, the results of previous diagrammatic T-matrix approaches are extended into the perturbatively inaccessible low energy regimes, and the long range (thermal) transport behaviour of the system is discussed. It turns out that in the extreme case of a half-filled tight binding band and infinitely strong impurities (impurities at the unitary limit), the system is in a delocalized phase.Comment: 14 pages, two figures include

Indentation size effect and 3D dislocation structure evolution in (001) oriented SrTiO3: HR‐ EBSD and etch‐pit analysis

Most crystalline materials exhibit an indentation size effect (ISE), i.e., an intrinsic increase in hardness with decreasing penetration depth. During indentation testing, the material underneath the indenter is heavily deformed, introducing strain gradients in the materials, causing high local dislocation densities. In the present work, the three-dimensional (3D) dislocation structure evolution and ISE in (001) oriented Strontium Titanate (STO) have been studied by direct observation of dislocations using chemical etching and high-resolution electron backscattered diffraction (HR-EBSD) analysis. The sequential polishing, etching and imaging technique was used to reveal the 3D dislocation etch-pit structure at various sub-surface depths using confocal laser and scanning electron microscopy (Fig. 1). The 3D dislocation etch-pit analysis of spherical indentations confirm that, at the early stage of plastic deformation, the dislocation pile-ups were aligned in \u3c100\u3e directions, lying on {110}45 planes, inclined at 45° to the (001) surface. At higher mean contact pressure and larger indentation depth, however, dislocation pile-ups along \u3c110\u3e directions appeared, lying on {110}90 planes, perpendicular to the (001) surface. These observations were qualitatively confirmed by corresponding direct Molecular Dynamics Simulations. Please click Additional Files below to see the full abstract

Ecological Factors and Historical Biogeography Influence the Evolutionary Divergence of Insular Rodents

<p>Islands have been the inspiration for some of evolutionary biology's most important advances. This is largely due to the unique properties of islands that promote the differentiation of island species from their mainland counterparts. Rodents are widely distributed across even the most remote islands, a rarity among mammals, making them uniquely suited to study the factors leading to the divergence of insular species. In this dissertation, I use two case studies to examine the morphological and genetic divergences that take place in an insular environment.</p><p>In chapters one and two, I examine how different factors influence insular body size change in rodents. In chapter one, I examine factors influencing the direction of island body size change using classification tree and random forest (CART) analyses. I observe strong consistency in the direction of size change within islands and within species, but little consistency at broader taxonomic scales. Including island and species traits in the CART analyses, I find mainland body mass to be the most important factor influencing size change. Other variables are significant, though their roles seem to be context-dependent.</p><p>In chapter two, I use the distributions of mainland rodent population body sizes to identify `extreme' insular rodent populations and compare traits associated with those populations and their islands with those island populations of a more typical size. I find that althought there is no trend among all insular rodents towards a larger or smaller size, `extreme' populations are more likely to increase in size. Using CART methods, I develop a predictive model for insular size change that identifies resource limitations as the main driver when insular rodent populations become `extremely small'. </p><p>Chapters three and four shift their focus to a single rodent species, the deer mouse <italic>Peromyscus maniculatus</italic>, as they examine the genetic differentiation of deer mice across the California Channel Islands and the nearby mainland. In chapter three, I sequence a region of the mitochondrial control region for individuals from 8 populations across the northern Channel Islands and two mainland sites, and I analyze these sequences by calculating population genetics parameters and creating a Bayesian inference tree and a statistical parsimony haplotype network. All of these analyses reveal significant divergences between island and mainland populations. Among the islands, Santa Barbara and Anacapa islands both display unique genetic signatures, but the other northern islands remain relatively undifferentiated.</p><p>In chapter four, I genotype individuals from the previous chapter at 5 microsatellite loci, I calculate additional population genetics parameters and I utilize a Bayesian clustering algorithm to examine the similarities and differences between nuclear and mitochondrial analyses. I find the nuclear data to be largely congruent with the mitochondrial analyses; there are significant differences between island and mainland populations, and Anacapa Island is significantly differentiated from the other islands. Unlike the previous analyses, Santa Barbara Island is not significantly different from the northern islands, yet San Miguel Island has a unique genetic signature. </p><p>These studies underscore the importance of ecological processes and historical biogeography in the generation of diversity, and they highlight the role of islands as drivers of evolutionary divergence.</p>Dissertatio

A review of experimental approaches to fracture toughness evaluation at the micro-scale

The discipline of fracture mechanics was born almost a century ago through the pioneering work of A.A. Griffith, and saw particularly rapid growth in the second half of 20th century when it became an indispensable tool in the development of advanced transportation, civil construction, and energy systems. Forty years ago, Materials & Design published a series of papers devoted to the state-of-the-art in the field of Fracture Mechanics. The present review reflects the lasting legacy and surviving importance of this theme: it is associated with the Virtual Special Issue on nanoscale materials testing and characterisation, and focuses on the modern experimental approaches to fine scale fracture toughness evaluation, with particular emphasis on micro-cantilever bending and micro-pillar splitting. The fundamental aspects of these approaches are overviewed, and their application to a range of systems is described. Implications for further development of these methods are discussed

Thermally activated processes in materials probed by nanoindentation - challenges, solutions, and insights

Nanoindentation experiments are widely used for assessing the local mechanical properties of materials. In recent years some new exciting developments were established for also analyzing thermally activated processes during deformation using indentation based techniques, namely nanoindentation strain rate jump and nanoindentation long term creep tests. For these different methods, control of the indenter tip movement as well as determination of the correct contact conditions are hugely important to assure reliable data. In fact, long term nanoindentation tests are prone to be strongly influenced by thermal drift, starting at room temperature but even more intensified for elevated temperatures. This talk will first focus on experimental issues and challenges, but also solutions during advanced nanoindentation testing to overcome thermal drift influences, as demonstrated for fused silica and ultra-fine grained (ufg) Au. Special focus will be on high temperature testing, different testing methodologies will be described, and it will be demonstrated how distinct indentation time and indentation depths related errors influence the basic results. In the second part different results on single crystal (sx) and ufg Cr but also on the intermetallic phase Mg17Al12 are presented. For Mg17Al12, it was observed that the deformation behavior, especially in terms of thermally activated processes, is significantly changing over temperature. While at room temperature up to 125°C deformation is dominated by jerky flow and a slight negative strain-rate sensitivity due to dislocation pinning and the Portevin - Le Chatelier effect, overcoming 150°C the material behaves remarkably different. In this regime the indentation data show significant ductile deformation behavior with large pile-up formation and a pronounced strain rate sensitivity in the superplastic regime, where the deformation is sustained by dislocation glide and climb. Sx and ufg Cr also show significant changes in deformation behavior with temperature. At ambient conditions, both microstructures show an enhanced strain-rate sensitivity due to the large thermally activated component in the flow stress. Overcoming the materials specific temperature Tc (~150°C for Cr) the behavior changes. For sx Cr the apparent strain-rate sensitivity diminishes completely, while for the ufg state the strain-rate sensitivity increases due to the increased importance of dislocation – grain boundary interactions paired with a change in the dominating deformation mechanism

Restoration of elective spine surgery during the first wave of COVID-19:a UK-wide British Association of Spine Surgeons (BASS) prospective, multicentre, observational study

AIMS: With resumption of elective spine surgery services in the UK following the first wave of the COVID-19 pandemic, we conducted a multicentre British Association of Spine Surgeons (BASS) collaborative study to examine the complications and deaths due to COVID-19 at the recovery phase of the pandemic. The aim was to analyze the safety of elective spinal surgery during the pandemic. METHODS: A prospective observational study was conducted from eight spinal centres for the first month of operating following restoration of elective spine surgery in each individual unit. Primary outcome measure was the 30-day postoperative COVID-19 infection rate. Secondary outcomes analyzed were the 30-day mortality rate, surgical adverse events, medical complications, and length of inpatient stay. RESULTS: In all, 257 patients (128 males) with a median age of 54 years (2 to 88) formed the study cohort. The mean number of procedures performed from each unit was 32 (16 to 101), with 118 procedures (46%) done as category three prioritization level. The majority of patients (87%) were low-medium “risk stratification” category and the mean length of hospital stay was 5.2 days. None of the patients were diagnosed with COVID-19 infection, nor was there any mortality related to COVID-19 during the 30-day follow-up period, with 25 patients (10%) having been tested for symptoms. Overall, 32 patients (12%) developed a total of 34 complications, with the majority (19/34) being grade 1 to 2 Clavien-Dindo classification of surgical complications. No patient required postoperative care in an intensive care setting for any unexpected complication. CONCLUSION: This study shows that safe and effective planned spinal surgical services can be restored avoiding viral transmission, with diligent adherence to national guidelines and COVID-19-secure pathways tailored according to the resources of the individual spinal units. Cite this article: Bone Jt Open 2021;2(12):1096–1101

Multi-hole gasoline direct injection:In-nozzle flow and primary breakup investigated in transparent nozzlesand with X-ray

The contribution describes the flow field inside modern gasoline direct-injection nozzles and sprays. Starting from the internal nozzle flow, results from transparent real-size nozzles are shown, where a significant vapor fraction even for cold fuel conditions is proven. Based on vapor fraction inside the nozzle, evidence for (super-)sonic flow conditions inside the nozzle is shown. The nozzle outlet velocity is determined by means of X-ray structure tracking velocimetry, which is a very powerful measurement technique to gain access to the very dense spray at the nozzle outlet. The X-ray velocities are compared to values that are determined by means of optical—phase Doppler anemometry/laser Doppler anemometry and Schlieren imaging—measurement techniques. By extrapolating the maximum droplet velocities found by laser Doppler anemometry in the more downstream regions of the spray to the nozzle outlet region, very similar velocities to the one derived from the X-ray measurements close to Bernoulli velocity are evaluated for typical gasoline direct-injection engine conditions. A third access to the nozzle outlet velocity is given by the derivation of penetration curves. The combination of vapor fractions and outlet velocities provides a measure for the initial spray momentum

Solid solution hardening in CrMnFeCoNi-based high entropy alloy systems studied by a combinatorial approach

Solid solution hardening in high entropy alloys was studied for the Cantor alloy using diffusion couples and nanoindentation. We study a continuous variation of the alloying content and directly correlate the nanoindentation hardness to the local composition up to the phase boundary. The composition dependent hardness is analysed using the Labusch model and the more recent Varvenne model. The Labusch model has been fitted to experimental data and confirms Cr as the most potent strengthening element. For comparison of the experimental hardness and the predicted yield strength of the Varvenne model, a concentration-dependent strain-hardening factor is introduced to account for strain hardening during indentation, which leads to a very good agreement between experiment and model. A study of the input parameters of the Varvenne model, performed by atomistic computer simulations, shows no significant effect of fluctuations in the atomic size misfit volumes or in the local shear modulus to the computed yield strength