A novel cell immunoassay to measure survival of motor neurons protein in blood cells

BACKGROUND: The motor neuron degenerative disease spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality and is caused by mutations in the survival of motor neurons (SMN) gene that reduce the expression levels of the SMN protein. A major goal of current therapeutic approaches is to increase SMN levels in SMA patients. The purpose of this study was to develop a reliable assay to measure SMN protein levels from peripheral blood samples. METHODS: We developed a novel cell immunoassay to quantitatively measure SMN levels from peripheral blood mononuclear cells (PBMCs) using a single anti-SMN antibody. RESULTS: SMN levels determined by the cell immunoassay are comparable to levels determined by Western blot, but in contrast, the immunoassay does not involve cell lysis, requires a small amount of patient material, and can be done on a large number of samples simultaneously. SMN levels from PBMCs are not influenced by cell type heterogeneity. CONCLUSION: SMN levels measured from total PBMCs provide an important snapshot of SMN protein expression, which should be a useful aid in SMA diagnosis, and a surrogate marker of efficacy of treatment in SMA clinical trials

Dynamical CP Violation in the Early Universe

Following earlier ideas of Dolgov, we show that the asymmetrical dynamical evolution of fields in the early Universe provides a new source for CP violation. This can lead to baryogenesis without any additional CP-violating interactions. The magnitude of this CP violation is time-dependent. In particular, it vanishes (or is very small) in the late Universe after the fields have relaxed (or are in their final approach) to their vacuum values. We provide an explicit example in which our mechanism is realized.Comment: 9 pages, latex, 1 figure (enclosed). The idea of the previous version was correct, but there were errors in its implementation. This has now been corrected -- some text modified, references added. Also, one author has been adde

An adherent tissue-inspired hydrogel delivery vehicle utilised in primary human glioma models.

A physical hydrogel cross-linked via the host-guest interactions of cucurbit[8]uril and utilised as an implantable drug-delivery vehicle for the brain is described herein. Constructed from hyaluronic acid, this hydrogel is biocompatible and has a high water content of 98%. The mechanical properties have been characterised by rheology and compared with the modulus of human brain tissue demonstrating the production of a soft material that can be moulded into the cavity it is implanted into following surgical resection. Furthermore, effective delivery of therapeutic compounds and antibodies to primary human glioblastoma cell lines is showcased by a variety of in vitro and ex vivo viability and immunocytochemistry based assays.This work was supported by The Brain Tumour Charity (RG89672), the National Institute for Health Research Cambridge Biomedical Research Centre; the Higher Education Funding Council for England. We acknowledge the Human Research Tissue Bank and Biomedical Research Centre for the tissue being accessed through the Human Research Tissue Bank. The Human Research Tissue Bank is supported by the NIHR Cambridge Biomedical Research Centre. MJR thanks the University of Cambridge Chemical Biology and Molecular Medicine PhD Training Programme for funding. CCP is thankful for the support of the EPSRC and the Brain Tumour Charity for funding. JHM acknowledges the support of the Gates Cambridge Scholarship programme. AKK was supported by a studentship from the John and Lucille van Geest Foundation

Can the Acceleration of Our Universe Be Explained by the Effects of Inhomogeneities?

No. It is simply not plausible that cosmic acceleration could arise within the context of general relativity from a back-reaction effect of inhomogeneities in our universe, without the presence of a cosmological constant or ``dark energy.'' We point out that our universe appears to be described very accurately on all scales by a Newtonianly perturbed FLRW metric. (This assertion is entirely consistent with the fact that we commonly encounter $\delta \rho/\rho > 10^{30}$.) If the universe is accurately described by a Newtonianly perturbed FLRW metric, then the back-reaction of inhomogeneities on the dynamics of the universe is negligible. If not, then it is the burden of an alternative model to account for the observed properties of our universe. We emphasize with concrete examples that it is {\it not} adequate to attempt to justify a model by merely showing that some spatially averaged quantities behave the same way as in FLRW models with acceleration. A quantity representing the ``scale factor'' may ``accelerate'' without there being any physically observable consequences of this acceleration. It also is {\it not} adequate to calculate the second-order stress energy tensor and show that it has a form similar to that of a cosmological constant of the appropriate magnitude. The second-order stress energy tensor is gauge dependent, and if it were large, contributions of higher perturbative order could not be neglected. We attempt to clear up the apparent confusion between the second-order stress energy tensor arising in perturbation theory and the ``effective stress energy tensor'' arising in the ``shortwave approximation.''Comment: 20 pages, 1 figure, several footnotes and references added, version accepted for publication in CQG;some clarifying comments adde

Witness and Worship in Pluralistic America

American society in the twenty- first century poses a myriad of challenges for the church as it seeks to be an effective witness to the Gospel of Jesus Christ. Among these challenges is an increasingly pluralistic cultural and religious context.https://scholar.csl.edu/ebooks/1040/thumbnail.jp

Training Impact on Novice and Experienced Research Coordinators

Competency-based training and professional development is critical to the clinical research enterprise. Understanding research coordinators’ perspectives is important for establishing a common core curriculum. The purpose of this study was to describe participants’ perspectives regarding the impact of online and classroom training sessions. 27 participants among three institutions, completed a two-day classroom training session. 10 novice and seven experienced research coordinators participated in focus group interviews. Grounded theory revealed similarities in novice and experienced coordinator themes including Identifying Preferences for Instruction and Changing Self Perceptions. Differences, seen in experienced participants, focused on personal change, in the theme of Re-Assessing Skills. Infrastructure and cultural issues were evident in their theme, Promoting Leadership and Advocacy. Novice participants recommended ways to improve training via their theme of Making Programmatic Improvements. Participants reported a clear preference for classroom learning. Training played an influential role in changing participants’ self-perceptions by validating their experiences. The findings provided guidance for developing a standardized curriculum. Training must be carefully tailored to the needs of participants while considering audience needs based on work experience, how technology can be used and offering content that is most urgently needed

Academic medical center clinical research professional workforce: Part 2 - issues in staff onboarding and professional development

Background: Defining key barriers to the development of a well-trained clinical research professional (CRP) workforce is an essential first step in identifying solutions for successful CRP onboarding, training, and competency development, which will enhance quality across the clinical and translational research enterprise. This study aimed to summarize barriers and best practices at academic medical centers related to effective CRP onboarding, training, professional development, identify challenges with the assessment of and mentoring for CRP competency growth, and describe opportunities to improve training and professionalization for the CRP career pathway. Materials/Methods: Qualitative data from a series of Un-Meeting breakout sessions and open-text survey questions were analyzed to explore the complex issues involved when developing high-quality onboarding and continuing education opportunities for CRPs at academic medical centers. Results: Results suggest there are several barriers to training the CRP workforce, including balancing foundational onboarding with role-based training, managing logistical challenges and institutional contexts, identifying/enlisting institutional champions, assessing competency, and providing high-quality mentorship. Several of these themes are interrelated. Two universal threads present throughout all themes are the need for effective communication and the need to improve professionalization of the CRP career pathway. Conclusion: Few institutions have solved all the issues related to training a competent and adaptable CRP workforce, although some have addressed one or more. We applied a socio-technical lens to illustrate our findings and the need for NCATS-funded academic medical centers to work collaboratively within and across institutions to overcome training barriers and support a vital, well-qualified workforce and present several exemplars from the field to help attain this goal

Triad representation of the Chern-Simons state in quantum gravity

We investigate a triad representation of the Chern-Simons state of quantum gravity with a non-vanishing cosmological constant. It is shown that the Chern-Simons state, which is a well-known exact wavefunctional within the Ashtekar theory, can be transformed to the real triad representation by means of a suitably generalized Fourier transformation, yielding a complex integral representation for the corresponding state in the triad variables. It is found that topologically inequivalent choices for the complex integration contour give rise to linearly independent wavefunctionals in the triad representation, which all arise from the one Chern-Simons state in the Ashtekar variables. For a suitable choice of the normalization factor, these states turn out to be gauge-invariant under arbitrary, even topologically non-trivial gauge-transformations. Explicit analytical expressions for the wavefunctionals in the triad representation can be obtained in several interesting asymptotic parameter regimes, and the associated semiclassical 4-geometries are discussed. In restriction to Bianchi-type homogeneous 3-metrics, we compare our results with earlier discussions of homogeneous cosmological models. Moreover, we define an inner product on the Hilbert space of quantum gravity, and choose a natural gauge-condition fixing the time-gauge. With respect to this particular inner product, the Chern-Simons state of quantum gravity turns out to be a non-normalizable wavefunctional.Comment: Latex, 30 pages, 1 figure, to appear in Phys. Rev.

A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease

Abstract Chronic graft-versus-host disease (cGVHD) is a major limitation of successful hematopoietic cell transplantation. The safety and efficacy of extracorporeal photopheresis (ECP) for 12 to 24 weeks together with standard therapy was compared with standard therapy alone in patients with cutaneous manifestations of cGVHD that could not be adequately controlled by corticosteroid treatment. The primary efficacy end point was a blinded quantitative comparison of percent change from baseline in Total Skin Score (TSS) of 10 body regions at week 12. Ninety-five patients were randomized to either ECP and standard therapy (n = 48) or standard therapy alone (n = 47). The median percentage improvement in TSS at week 12 was 14.5% for the ECP arm and 8.5% for the control arm (P = .48). The proportion of patients who had at least a 50% reduction in steroid dose and at least a 25% decrease from baseline in TSS was 8.3% in the ECP arm at week 12 and 0% in the control arm (P = .04). The nonblinded investigator assessment of skin complete or partial responses revealed a significant improvement in favor of ECP (P < .001). ECP was generally well tolerated. These results suggest that ECP may have a steroid-sparing effect in the treatment of cGVHD. Clinical trials registered at www.ClinicalTrials.gov as NCT00054613