Ultrasmall silica nanoparticles directly ligate the T cell receptor complex.

The impact of ultrasmall nanoparticles (<10-nm diameter) on the immune system is poorly understood. Recently, ultrasmall silica nanoparticles (USSN), which have gained increasing attention for therapeutic applications, were shown to stimulate T lymphocytes directly and at relatively low-exposure doses. Delineating underlying mechanisms and associated cell signaling will hasten therapeutic translation and is reported herein. Using competitive binding assays and molecular modeling, we established that the T cell receptor (TCR):CD3 complex is required for USSN-induced T cell activation, and that direct receptor complex-particle interactions are permitted both sterically and electrostatically. Activation is not limited to αβ TCR-bearing T cells since those with γδ TCR showed similar responses, implying that USSN mediate their effect by binding to extracellular domains of the flanking CD3 regions of the TCR complex. We confirmed that USSN initiated the signaling pathway immediately downstream of the TCR with rapid phosphorylation of both ζ-chain-associated protein 70 and linker for activation of T cells protein. However, T cell proliferation or IL-2 secretion were only triggered by USSN when costimulatory anti-CD28 or phorbate esters were present, demonstrating that the specific impact of USSN is in initiation of the primary, nuclear factor of activated T cells-pathway signaling from the TCR complex. Hence, we have established that USSN are partial agonists for the TCR complex because of induction of the primary T cell activation signal. Their ability to bind the TCR complex rapidly, and then to dissolve into benign orthosilicic acid, makes them an appealing option for therapies targeted at transient TCR:CD3 receptor binding.These studies were supported by grants from the UK Medical Research Council (Grant number MR/R005699/1) and the Natural Sciences and Engineering Research Council of Canada, as well as through sponsorship from HS Pharmaceuticals LLC

The effectiveness of non-native fish removal techniques in freshwater ecosystems: a systematic review

In aquatic systems, biological invasions can result in adverse ecological effects. Man-agement techniques available for non-native fish removal programs (including eradica-tion and population size control) vary widely, but include chemicals, harvest regimes, physical removal, or biological control. For management agencies, deciding on what non-native fish removal program to use has been challenging because there is little reliable information about the relative effectiveness of these measures in controlling or eradicat-ing non-native fish. We conducted a systematic review, including a critical appraisal of study validity, to assess the effectiveness of different non-native fish removal methods, and to identify the factors that influence the overall success rate of each type of method. We found 95 relevant studies, generating 158 data sets. The evidence base was dominated by poorly documented studies with inadequate experimental designs (76% of removal projects). When the management goal was non-native fish eradication, chemical treat-ments were relatively successful (antimycin 89%; rotenone 75%) compared to other in-terventions. Electrofishing and passive removal measure studies indicated successful eradication was possible (58% each respectively) but required intensive effort and multi-ple treatments over a number of years. Of these studies with sufficient information, elec-trofishing had the highest success for population size control (56% of data sets). Overall, inadequate data quality and completeness severely limited our ability to make strong con-clusions about the relationships between non-native fish abundance and different methods of eradication and population control, and the factors influencing the overall success rate of each method. Our review highlights that there is considerable scope for improving our evaluations of non-native fish removal methods. It is recommended that programs should have explicitly stated objectives, better data reporting, and study designs that (when pos-sible and appropriate) incorporate replicated and controlled investigations with rigorous, long-term quantitative monitoring. Future research on the effectiveness of non-native fish removal methods should focus on: (1) the efficacy of existing or potentially new removal measures in larger, more complex environments; (2) a broader range of removal measures in general, and (3) phenotypic characteristics of individual fish within a population that fail to be eradicated or controlled

Systematic overviews of partnership principles and strategies identified from health research about spinal cord injury and related health conditions:A scoping review

Study design: Scoping review.Objective: To identify and provide systematic overviews of partnership principles and strategies identified from health research about spinal cord injury (SCI) and related health conditions.Methods: Four health electronic databases (Medline, Embase, CINAHL, PsycINFO) were searched from inception to March 2019. We included articles that described, reflected, and/or evaluated one or more collaborative research activities in health research about SCI, stroke, multiple sclerosis, Parkinson's disease, amputation, cerebral palsy, spina bifida, amyotrophic lateral sclerosis, acquired brain injury, or wheelchair-users. Partnership principles (i.e. norms or values) and strategies (i.e. observable actions) were extracted and analyzed using directed qualitative content analysis.Results: We included 39 articles about SCI (n = 13), stroke (n = 15), multiple sclerosis (n = 5), amputation (n = 2), cerebral palsy (n = 2), Parkinson's disease (n = 1), and wheelchair users (n = 1). We extracted 110 principles and synthesized them into 13 overarching principles. Principles related to building and maintaining relationships between researchers and research users were most frequently reported. We identified 32 strategies that could be applied at various phases of the research process and 26 strategies that were specific to a research phase (planning, conduct, or dissemination).Conclusion: We provided systematic overviews of principles and strategies for research partnerships. These could be used by researchers and research users who want to work in partnership to plan, conduct and/or disseminate their SCI research. The findings informed the development of the new SCI Integrated Knowledge Translation Guiding Principles (www.iktprinciples.com) and will support the implementation of these Principles within the SCI research system.</p

Dependence of Intramyocardial Pressure and Coronary Flow on Ventricular Loading and Contractility: A Model Study

The phasic coronary arterial inflow during the normal cardiac cycle has been explained with simple (waterfall, intramyocardial pump) models, emphasizing the role of ventricular pressure. To explain changes in isovolumic and low afterload beats, these models were extended with the effect of three-dimensional wall stress, nonlinear characteristics of the coronary bed, and extravascular fluid exchange. With the associated increase in the number of model parameters, a detailed parameter sensitivity analysis has become difficult. Therefore we investigated the primary relations between ventricular pressure and volume, wall stress, intramyocardial pressure and coronary blood flow, with a mathematical model with a limited number of parameters. The model replicates several experimental observations: the phasic character of coronary inflow is virtually independent of maximum ventricular pressure, the amplitude of the coronary flow signal varies about proportionally with cardiac contractility, and intramyocardial pressure in the ventricular wall may exceed ventricular pressure. A parameter sensitivity analysis shows that the normalized amplitude of coronary inflow is mainly determined by contractility, reflected in ventricular pressure and, at low ventricular volumes, radial wall stress. Normalized flow amplitude is less sensitive to myocardial coronary compliance and resistance, and to the relation between active fiber stress, time, and sarcomere shortening velocity

Optimal Fleet Composition via Dynamic Programming and Golden Section Search

In this paper, we consider an optimization problem arising in vehicle fleet management. The problem is to construct a heterogeneous vehicle fleet in such a way that cost is minimized subject to a constraint on the overall fleet size. The cost function incorporates fixed and variable costs associated with the fleet, as well as hiring costs that are incurred when vehicle requirements exceed fleet capacity. We first consider the simple case when there is only one type of vehicle. We show that in this case the cost function is convex, and thus the problem can be solved efficiently using the well-known golden section method. We then devise an algorithm, based on dynamic programming and the golden section method, for solving the general problem in which there are multiple vehicle types. We conclude the paper with some simulation results

On the Origin of Regioselectivity in Palladium-Catalyzed Oxidation of Glucosides

The palladium-catalyzed oxidation of glucopyranosides has been investigated using relativistic density functional theory (DFT) at ZORA-BLYP−D3(BJ)/TZ2P. The complete Gibbs free energy profiles for the oxidation of secondary hydroxy groups at C2, C3, and C4 were computed for methyl β-glucoside and methyl carba-β-glucoside. Both computations and oxidation experiments on carba-glucosides demonstrate the crucial role of the ring oxygen in the C3 regioselectivity observed during the oxidation of glucosides. Analysis of the model systems for oxidized methyl β-glucoside shows that the C3 oxidation product is intrinsically favored in the presence of the ring oxygen. Subsequent energy decomposition analysis (EDA) and Hirschfeld charge analysis reveal the role of the ring oxygen: it positively polarizes C1/C5 by inductive effects and disfavors any subsequent buildup of positive charge at neighboring carbon atoms, rendering C3 the most favored site for the β-hydride elimination

Sleep spindle and slow wave frequency reflect motor skill performance in primary school-age children

Background and Aim: The role of sleep in the enhancement of motor skills has been studied extensively in adults. We aimed to determine involvement of sleep and characteristics of spindles and slow waves in a motor skill in children. Hypothesis: We hypothesized sleep-dependence of skill enhancement and an association of interindividual differences in skill and sleep characteristics. Methods:: 30 children (19 females, 10.7 ± 0.8 years of age; mean ± SD) performed finger sequence tapping tasks in a repeated-measures design spanning 4 days including 1 polysomnography (PSG) night. Initial and delayed performance were assessed over 12 h of wake; 12 h with sleep; and 24 h with wake and sleep. For the 12 h with sleep, children were assigned to one of three conditions: modulation of slow waves and spindles was attempted using acoustic perturbation, and compared to yoked and no-sound control conditions. Analyses: Mixed effect regression models evaluated the association of sleep, its macrostructure and spindles and slow wave parameters with initial and delayed speed and accuracy. Results and Conclusions: Children enhance their accuracy only over an interval with sleep. Unlike previously reported in adults, children enhance their speed independent of sleep, a capacity that may to be lost in adulthood. Individual differences in the dominant frequency of spindles and slow waves were predictive for performance: children performed better if they had less slow spindles, more fast spindles and faster slow waves. On the other hand, overnight enhancement of accuracy was most pronounced in children with more slow spindles and slower slow waves, i.e., the ones with an initial lower performance. Associations of spindle and slow wave characteristics with initial performance may confound interpretation of their involvement in overnight enhancement. Slower frequencies of characteristic sleep events may mark slower learning and immaturity of networks involved in motor skills

Treatment with intravenous pamidronate is a good alternative in case of gastrointestinal side effects or contraindications for oral bisphosphonates

<p>Abstract</p> <p>Background</p> <p>In case of contraindications or intolerance during treatment with oral bisphosphonates (OB), administration of pamidronate intravenously is a widely used alternative.</p> <p>In this study we compared the effect on change in bone mineral density (BMD) of the spine and hip during long term treatment with pamidronate iv in comparison to OB.</p> <p>Methods</p> <p>We studied 61 patients receiving treatment for at least two years. In case of contraindications or intolerance (within 3 months) of an OB, pamidronate iv was started. BMD was measured on a Hologic 4500 and a Lunar DPX-IQ at the spine (L1-L4) and total hip.</p> <p>Results</p> <p>Thirty-one patients were enrolled in the OB group and 30 in the intravenous pamidronate group. Mean follow-up duration (SD) was 4.3 (1.3) years. We observed a significant increase (p < 0.001) in spinal BMD, both in the OB group (8.3%) as well as in the pamidronate iv group (6.1%), but no significant difference in BMD change between the OB and pamidronate iv groups. At the hips, we observed a tendency to increased BMD in both groups, 1.1% in the OB and 1.4% in the pamidronate iv group.</p> <p>Conclusion</p> <p>We conclude that intravenous pamidronate is a good alternative for oral bisphosphonates in the treatment of osteoporosis in patients with contraindications or intolerance during treatment with oral bisphosphonates.</p

Judging parental competence: A cross‐country analysis of judicial decision makers' written assessment of mothers' parenting capacities in newborn removal cases

This paper examines the discretionary reasoning of the judiciary in three jurisdictions, England, Germany and Norway, in cases deciding whether a newborn child is safe with her parents or intervention is necessary. Our analysis focuses on one specific dimension of decision makers' exercise of discretion, namely, if and how the strengths and weaknesses of the mother are considered. The data material consists of all decisions concerning care orders of newborns from one large city in Germany from 2015 to 2017 (n = 27) and 2016 in Norway (n = 76) and all publicly available newborn removal decisions in England for 2015–2017 (n = 14). The findings reveal a high number of risk factors in the cases and less focus on risk‐reducing factors. The situation of the newborn is considered to be harmful, as most cases result in a care order. Judicial discretion differs by how much information, and what types of factors, are included in the justification for the decision. A learning point for decision makers and policymakers would be to actively undertake a balancing act between risk‐increasing and risk‐reducing factors.publishedVersio

Грунти як об’єкт науки

Висвітлюються деякі аспекти розвитку наших уявлень про ґрунтознавство як науковий напрямок природознавства та про ґрунти як об’єкт науки.Освещаются некоторые аспекты развития наших представлений о почвоведении как научном направлении природоведения и о почвах как объекте науки.The author highlights several aspects of human knowledge about soil research as a field of natural science, and about soils as a research object