Characterization of the Response of Primary Cells Relevant to Dialysis-Related Amyloidosis to β2-Microglobulin Monomer and Fibrils

The formation of insoluble amyloid fibrils is associated with an array of devastating human diseases. Dialysis-related amyloidosis (DRA) is a severe complication of hemodialysis that results in the progressive destruction of the bones and joints. Elevated concentrations of β2-microglobulin (β2m) in the serum of subjects on hemodialysis promote the formation of amyloid fibrils in the osteoarticular tissues, but the cellular basis for the destruction of these tissues in DRA is poorly understood. In this study we performed a systematic analysis of the interaction of monomeric and fibrillar β2m with primary human cells of the types present in the synovial joints of subjects with DRA. Building upon observations that macrophages infiltrate β2m amyloid deposits in vivo we demonstrate that monocytes, the precursors of macrophages, cannot degrade β2m fibrils, and that both monomeric β2m and fibrillar β2m are cytotoxic to these cells. β2m fibrils also impair the formation of bone resorbing osteoclasts from monocytes and reduce the viability of osteoblasts, the cell type that produces bone. As a consequence, we predict that β2m amyloid will disrupt the remodelling of the bone, which is critical for the maintenance of this tissue. Moreover, we show that β2m fibrils reduce the viability of chondrocytes, rationalizing the loss of cartilage in DRA. Together, our observations demonstrate that β2m cytotoxicity has multiple cellular targets in the osteoarticular tissues and is likely to be a key factor in the bone and joint destruction characteristic of DRA

Creativity as a Matter of Choice: Prior Experience and Task Instruction as Boundary Conditions for the Positive Effect of Choice on Creativity

This study investigates the effects of prior experience, task instruction, and choice on creative performance. Although extant research suggests that giving people choice in how they approach a task could enhance creative performance, we propose that this view needs to be circumscribed. Specifically, we argue that when choice is administered during problem solving by varying the number of available resources, the high combinatorial flexibility conferred by a large choice set of resources can be overwhelming. Through two experiments, we found that only individuals with high prior experience in the task domain and given explicit instruction to be creative produced more creative outcomes when given more choice. When either of these two conditions is not met (i.e., low prior experience or given non-creativity instruction), more choice did not lead to more creative performance. Theoretical and practical implications of these findings are discussed

Solvation effects, structural, vibrational analysis, chemical reactivity, nanocages, ELF, LOL, docking and MD simulation on Sitagliptin

Sitagliptin is a medication used to manage type-2 diabetes. The present study investigates the experimental and theoretical results of Sitagliptin (SG). Density functional theory (DFT) calculations were used to determine optimized parameters at the B3LYP functional /6-31++G(d,p) basis set. In addition Time-dependent DFT is used to compute excited states of SG and SG-Ag6 and predict UV spectra. The electronic properties of silver nano cages containing SG have exhibited a notable enhancement. Natural bond orbital (NBO) analysis was also used to determine charge transfer within the molecule and stabilization energy. Electronic properties such as molecular electrostatic potential (MEP), frontier molecular orbital (FMO) analysis of SG and SG-Ag6 were investigated. The chemical significance of SG has been discussed using electron localization function (ELF) and local orbital locator functions (LOL) with contour images. Sitagliptin appears to have promise as a treatment for the chosen inhibitors, according to the docking binding affinities and the formation of a significant amount of hydrogen bonds. The molecular dynamics simulations were also performed using Gromacs 5.1.3 and discussed

Modulation of murine olivary connexin 36 gap junctions by PKA and CaMKII

The inferior olive (IO) is a nucleus located in the brainstem and it is part of the olivo-cerebellar loop. This circuit plays a fundamental role in generation and acquisition of coherent motor patterns and it relies on synchronous activation of groups of Purkinje cells (PC) in the cerebellar cortex. IO neurons integrate their intrinsic oscillatory activity with excitatory inputs coming from the somatosensory system and inhibitory feedback coming from the cerebellar nuclei. Alongside these chemical synaptic inputs, IO neurons are coupled to one another via connexin 36 (Cx36) containing gap junctions (GJs) that create a functional syncytium between neurons. Communication between olivary neurons is regulated by these GJs and their correct functioning contributes to coherent oscillations in the IO and proper motor learning. Here, we explore the cellular pathways that can regulate the coupling between olivary neurons. We combined in vitroelectrophysiology and immunohistochemistry (IHC) on mouse acute brain slices to unravel the pathways that regulate olivary coupling. We found that enhancing the activity of the protein kinase A (PKA) pathway and blocking the Ca2+/calmodulin-dependent protein kinase II (CaMKII) pathway can both down-regulate the size of the coupled network. However, these two kinases follow different mechanisms of action. Our results suggest that activation of the PKA pathway reduces the opening probability of the Cx36 GJs, whereas inhibition of the CaMKII pathway reduces the number of Cx36 GJs. The low densities of Cx36 proteins and electrical synapses in βCaMKII knock-out mice point towards an essential role for this protein kinase in regulating the density of GJs in the IO. Thus, the level of olivary coupling is a dynamic process and regulated by a variety of enzymes modulating GJs expression, docking and activity

Achieving flying colours in surgical safety: audit of World Health Organization 'Surgical Safety Checklist' compliance

Objective: The World Health Organization 'Surgical Safety Checklist' has been adopted by UK surgical units following National Patient Safety Agency guidance. Our aim was to assess compliance with our local version of this Checklist. Methods: Otolaryngology trainee doctors prospectively assessed compliance with the local Checklist over a six-week period. A staff educational intervention was implemented and the audit was repeated 12 months later. Results: A total of 72 cases were assessed. The initial audit found that: 44 per cent of procedures were undocumented at 'Sign in'; 'Time out' was inappropriately interrupted in 39 per cent of cases; the procedure started before Checklist completion in 33 per cent of cases; and the 'Sign out' was not read out in 94 per cent of cases and was not fully documented in 42 per cent of cases. Following education, re-audit indicated that overall compliance had improved from 63.7 per cent (±8.9 per cent standard error of the mean) to 90.4 per cent (±2.7 per cent standard error of the mean). Conclusion: Our completed audit cycle demonstrated a significant improvement in Checklist compliance following educational intervention. We discuss barriers to compliance, as well as strategies for quality improvement, and we call for other surgeons to similarly publish their Checklist experience and assess its impact on surgical outcomes

Useful parameters for distinguishing nonalcoholic steatohepatitis with mild steatosis from cryptogenic chronic hepatitis in the Japanese population

The definitive version is available at www.blackwell-synergy.com.ArticleLIVER INTERNATIONAL. 26(8): 956-963 (2006)journal articl

Insights into solvation effects, spectroscopic, Hirshfeld surface Analysis, reactivity analysis and anti-Covid-19 ability of doxylamine succinate: Experimental, DFT, MD and docking simulations

In the present work, the experimental and theoretical reports on electronic and vibrational features of doxylamine succinate (DXS) are presented. The vibrational spectra were documented and wavenumbers were obtained theoretically assigned by means of potential energy distribution. In DXS, N-H…O and C-H…O intermolecular hydrogen bonding contacts are associated with O…H/H…O interactions. Solvation free energy (SFE) for DXS in water, methanol and DMSO, are −10.67, −10.95 and −10.61 eV/mol respectively. Interpretation of electrostatic potential, electron localization function (ELF), localized orbital locator (LOL) as well as atoms-in-molecules (AIM) analysis is also performed. Presence of non-covalent interactions is evident from the non-covalent interaction (NCI) isosurface. Molecular docking and simulations were used to determine the binding energy of DXS in order to investigate its potential activity against the SARS-CoV-2 protease

Detection of pulse trains in the electrically stimulated cochlea: Effects of cochlear health

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98659/1/JAS003954.pd