Crystallization of human gelsolin

AbstractHuman gelsolin has been crystallized by microdialysis techniques to give single crystals that diffract to 3.5 Å resolution. The crystals belong to space group P4212 and have cell dimensions a = 175.0 Å, c = 151.6 Å. They contain two gelsolin molecules in the asymmetric unit

Validating criteria for identifying core concepts using many-facet rasch measurement

Introduction: Core concepts are foundational, discipline-based ideas considered necessary for students to learn, remember, understand, and apply. To evaluate the extent to which a concept is “core,” experts often rate concepts using various criteria, such as importance, complexity, and timeliness. However, there is a lack of validity evidence for core concepts criteria. Methods: Using a three-facet Many-Facet Rasch Measurement (MFRM) model, we analyzed 7,558 ratings provided by 21 experts/raters for 74 pharmacology core concepts using five criteria measured on a five-point scale. Results: All of the criteria had Infit or Outfit MnSq values within the expected range (0.5 < MnSq < 1.7), suggesting the criteria contained an acceptable amount of variability; a reliability index of approximately 1.00 suggested that the criteria were reliably separated with a high degree of confidence. The rating scale Outfit MnSq statistics also fell within the 0.5–1.7 model fit limits; the “average measure” and “Rasch-Andrich thresholds” increased in magnitude as the rating scale categories increased, suggesting that core concepts with higher ratings were in fact meeting the criteria more convincingly than those with lower ratings. Adjusting expert ratings using the MFRM facets (e.g., rater severity) resulted in reorganization of core concepts rankings. Conclusion: This paper is a novel contribution to core concepts research and is intended to inform other disciplines seeking to develop, implement, and refine core concepts within the biomedical sciences and beyond

Expression of rabbit IL-4 by recombinant myxoma viruses enhances virulence and overcomes genetic resistance to myxomatosis

AbstractRabbit IL-4 was expressed in the virulent standard laboratory strain (SLS) and the attenuated Uriarra (Ur) strain of myxoma virus with the aim of creating a Th2 cytokine environment and inhibiting the development of an antiviral cell-mediated response to myxomatosis in infected rabbits. This allowed testing of a model for genetic resistance to myxomatosis in wild rabbits that have undergone 50 years of natural selection for resistance to myxomatosis. Expression of IL-4 significantly enhanced virulence of both virulent and attenuated virus strains in susceptible (laboratory) and resistant (wild) rabbits. SLS-IL-4 completely overcame genetic resistance in wild rabbits. The pathogenesis of SLS-IL-4 was compared in susceptible and resistant rabbits. The results support a model for resistance to myxomatosis of an enhanced innate immune response controlling virus replication and allowing an effective antiviral cell-mediated immune response to develop in resistant rabbits. Expression of IL-4 did not overcome immunity to myxomatosis induced by immunization

Incomplete inverse spectral and nodal problems for differential pencils

[[abstract]]We prove uniqueness theorems for so-called half inverse spectral problem (and also for some its modification) for second order differential pencils on a finite interval with Robin boundary conditions. Using the obtained result we show that for unique determination of the pencil it is sufficient to specify the nodal points only on a part of the interval slightly exceeding its half.[[notice]]補正完畢[[incitationindex]]SCI[[booktype]]紙本[[booktype]]電子

Combined Decision Techniques for the Existential Theory of the Reals

Methods for deciding quantifier-free non-linear arithmetical conjectures over *** are crucial in the formal verification of many real-world systems and in formalised mathematics. While non-linear (rational function) arithmetic over *** is decidable, it is fundamentally infeasible: any general decision method for this problem is worst-case exponential in the dimension (number of variables) of the formula being analysed. This is unfortunate, as many practical applications of real algebraic decision methods require reasoning about high-dimensional conjectures. Despite their inherent infeasibility, a number of different decision methods have been developed, most of which have &quot;sweet spots&quot; --- e.g., types of problems for which they perform much better than they do in general. Such &quot;sweet spots&quot; can in many cases be heuristically combined to solve problems that are out of reach of the individual decision methods when used in isolation. RAHD (&quot;Real Algebra in High Dimensions&quot;) is a theorem prover that works to combine a collection of real algebraic decision methods in ways that exploit their respective &quot;sweet-spots.&quot; We discuss high-level mathematical and design aspects of RAHD and illustrate its use on a number of examples

3D-printed micro lens-in-lens for in vivo multimodal microendoscopy

Published online: March 1, 2022Multimodal microendoscopes enable co-located structural and molecular measurements in vivo, thus providing useful insights into the pathological changes associated with disease. However, different optical imaging modalities often have conflicting optical requirements for optimal lens design. For example, a high numerical aperture (NA) lens is needed to realize high-sensitivity fluorescence measurements. In contrast, optical coherence tomography (OCT) demands a low NA to achieve a large depth of focus. These competing requirements present a significant challenge in the design and fabrication of miniaturized imaging probes that are capable of supporting high-quality multiple modalities simultaneously. An optical design is demonstrated which uses two-photon 3D printing to create a miniaturized lens that is simultaneously optimized for these conflicting imaging modalities. The lens-in-lens design contains distinct but connected optical surfaces that separately address the needs of both fluorescence and OCT imaging within a lens of 330 µm diameter. This design shows an improvement in fluorescence sensitivity of >10x in contrast to more conventional fiber-optic design approaches. This lens-in-lens is then integrated into an intravascular catheter probe with a diameter of 520 µm. The first simultaneous intravascular OCT and fluorescence imaging of a mouse artery in vivo is reported.Jiawen Li, Simon Thiele, Rodney W. Kirk, Bryden C. Quirk, Ayla Hoogendoorn, Yung Chih Chen, Karlheinz Peter, Stephen J. Nicholls, Johan W. Verjans, Peter J. Psaltis, Christina Bursill, Alois M. Herkommer, Harald Giessen, and Robert A. McLaughli

Cross-reactive probes on Illumina DNA methylation arrays: a large study on ALS shows that a cautionary approach is warranted in interpreting epigenome-wide association studies

Illumina DNA methylation arrays are a widely used tool for performing genome-wide DNA methylation analyses. However, measurements obtained from these arrays may be affected by technical artefacts that result in spurious associations if left unchecked. Cross-reactivity represents one of the major challenges, meaning that probes may map to multiple regions in the genome. Although several studies have reported on this issue, few studies have empirically examined the impact of cross-reactivity in an epigenome-wide association study (EWAS). In this paper, we report on cross-reactivity issues that we discovered in a large EWAS on the presence of the C9orf72 repeat expansion in ALS patients. Specifically, we found that that the majority of the significant probes inadvertently cross-hybridized to the C9orf72 locus. Importantly, these probes were not flagged as cross-reactive in previous studies, leading to novel insights into the extent to which cross-reactivity can impact EWAS. Our findings are particularly relevant for epigenetic studies into diseases associated with repeat expansions and other types of structural variation. More generally however, considering that most spurious associations were not excluded based on pre-defined sets of cross-reactive probes, we believe that the presented data-driven flag and consider approach is relevant for any type of EWAS

Multiwavelength studies of MHD waves in the solar chromosphere: An overview of recent results

The chromosphere is a thin layer of the solar atmosphere that bridges the relatively cool photosphere and the intensely heated transition region and corona. Compressible and incompressible waves propagating through the chromosphere can supply significant amounts of energy to the interface region and corona. In recent years an abundance of high-resolution observations from state-of-the-art facilities have provided new and exciting ways of disentangling the characteristics of oscillatory phenomena propagating through the dynamic chromosphere. Coupled with rapid advancements in magnetohydrodynamic wave theory, we are now in an ideal position to thoroughly investigate the role waves play in supplying energy to sustain chromospheric and coronal heating. Here, we review the recent progress made in characterising, categorising and interpreting oscillations manifesting in the solar chromosphere, with an impetus placed on their intrinsic energetics.Comment: 48 pages, 25 figures, accepted into Space Science Review

C9orf72 expansion differentially affects males with spinal onset amyotrophic lateral sclerosis.

INTRODUCTION: The C9orf72 repeat expansion has been reported as a negative prognostic factor in amyotrophic lateral sclerosis (ALS). We have examined the prognostic impact of the C9orf72 repeat expansion in European subgroups based on gender and site of onset. METHODS: C9orf72 status and demographic/clinical data from 4925 patients with ALS drawn from 3 prospective ALS registers (Ireland, Italy and the Netherlands), and clinical data sets in the UK and Belgium. Flexible parametric survival models were built including known prognostic factors (age, diagnostic delay and site of onset), gender and the presence of an expanded repeat in C9orf72. These were used to explore the effects of C9orf72 on survival by gender and site of onset. Individual patient data (IPD) meta-analysis was used to estimate HRs for results of particular importance. RESULTS: 457 (8.95%) of 4925 ALS cases carried the C9orf72 repeat expansion. A meta-analysis of C9orf72 estimated a survival HR of 1.36 (1.18 to 1.57) for those carrying the expansion. Models evaluating interaction between gender and C9orf72 repeat expansions demonstrated that the reduced survival due to C9orf72 expansion was being driven by spinal onset males (HR 1.56 (95% CI 1.25 to 1.96). CONCLUSIONS: This study represents the largest combined analysis of the prognostic characteristics of the C9orf72 expansion. We have shown for the first time that the negative prognostic implication of this variant is driven by males with spinal onset disease, indicating a hitherto unrecognised gender-mediated effect of the variant that requires further exploration