Impact of serotonin 2C receptor null mutation on physiology and behavior associated with nigrostriatal dopamine pathway function

The impact of serotonergic neurotransmission on brain dopaminergic pathways has substantial relevance to many neuropsychiatric disorders. A particularly prominent role has been ascribed to the inhibitory effects of serotonin 2C receptor (5-HT2CR) activation on physiology and behavior mediated by the mesolimbic dopaminergic pathway, particularly in the terminal region of the nucleus accumbens. The influence of this receptor subtype on functions mediated by the nigrostriatal dopaminergic pathway is less clear. Here we report that a null mutation eliminating expression of 5-HT2CRs produces marked alterations in the activity and functional output of this pathway. 5-HT2CR mutant mice displayed increased activity of substantia nigra pars compacta (SNc) dopaminergic neurons, elevated baseline extracellular dopamine concentrations in the dorsal striatum (DSt), alterations in grooming behavior, and enhanced sensitivity to the stereotypic behavioral effects of D-amphetamine and GBR 12909. These psychostimulant responses occurred in the absence of phenotypic differences in drug-induced extracellular dopamine concentration, suggesting a phenotypic alteration in behavioral responses to released dopamine. This was further suggested by enhanced behavioral responses of mutant mice to the D1 receptor agonist SKF 81297. Differences in DSt D1 or D2 receptor expression were not found, nor were differences in medium spiny neuron firing patterns or intrinsic membrane properties following dopamine stimulation. We conclude that 5-HT2CRs regulate nigrostriatal dopaminergic activity and function both at SNc dopaminergic neurons and at a locus downstream of the DSt.peer-reviewe

Effect of autolysis on the specificity of bovine spongiform encephalopathy rapid tests

<p>Abstract</p> <p>Background</p> <p>Routine rapid testing for Bovine Spongiform Encephalopathy (BSE) has highlighted some problems with BSE rapid test performance, the most significant being the number of initially reactive samples and the false positive results on autolyzed tissue. This point is important for BSE active surveillance in risk populations, because tissue autolysis is often unavoidable in routine cases. A robust test suitable for use on field material is therefore needed. To date, very limited information regarding the effect of autolysis on the robustness of rapid tests has been documented; therefore, the National Reference Centre for Animal Encephalopathies (CEA) rapid test laboratory selected 450 autolyzed and negative brain stem samples from fallen stock bovines older than 24 months to assess the specificity of four tests approved for BSE active surveillance: Biorad TeSeE, Enfer TSE version 2.0, Prionics^®Check LIA, and IDEXX Herd Check BSE Antigen Kit EIA. The samples were graded according to the degree of autolysis and then dissected into five portions, four of which randomly assigned to processing by rapid tests and one to be available for confirmatory Western blot analysis.</p> <p>Findings</p> <p>The specificity of the four systems was 100% for all three grades of autolysis, while the percentage of initially reactive results was 0.00 (95%CI 0.00-0.82), 0.22 (95%CI 0.006-1.23), 0.44 (95%CI 0.05-1.60), and 0.89 (95%CI 0.24-2.26) for the Biorad TeSeE, the Prionics^®Check LIA, the IDEXX Herd Check BSE and the Enfer TSE tests, respectively. No association with the degree of autolysis could be drawn.</p> <p>Conclusions</p> <p>The present study demonstrates that the four rapid tests can be considered well-running diagnostic tools regardless of tissue quality; nevertheless, the number of initial reactive samples reported for some systems must not be underestimated in routine testing.</p> <p>Furthermore the compliance with the reported performance can be guaranteed only when an ongoing high careful batch quality control system is in place.</p

The ABC130 barrel module prototyping programme for the ATLAS strip tracker

For the Phase-II Upgrade of the ATLAS Detector, its Inner Detector, consisting of silicon pixel, silicon strip and transition radiation sub-detectors, will be replaced with an all new 100 % silicon tracker, composed of a pixel tracker at inner radii and a strip tracker at outer radii. The future ATLAS strip tracker will include 11,000 silicon sensor modules in the central region (barrel) and 7,000 modules in the forward region (end-caps), which are foreseen to be constructed over a period of 3.5 years. The construction of each module consists of a series of assembly and quality control steps, which were engineered to be identical for all production sites. In order to develop the tooling and procedures for assembly and testing of these modules, two series of major prototyping programs were conducted: an early program using readout chips designed using a 250 nm fabrication process (ABCN-25) and a subsequent program using a follow-up chip set made using 130 nm processing (ABC130 and HCC130 chips). This second generation of readout chips was used for an extensive prototyping program that produced around 100 barrel-type modules and contributed significantly to the development of the final module layout. This paper gives an overview of the components used in ABC130 barrel modules, their assembly procedure and findings resulting from their tests.Comment: 82 pages, 66 figure

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Patterns of etanercept use in juvenile idiopathic arthritis in the Childhood Arthritis and Rheumatology Research Alliance Registry

Abstract Background We aimed to characterize etanercept (ETN) use in juvenile idiopathic arthritis (JIA) patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Registry. Methods The CARRA Registry is a convenience cohort of patients with paediatric onset rheumatic diseases, including JIA. JIA patients treated with ETN for whom the month and year of ETN initiation were available were included. Patterns of ETN and methotrexate (MTX) use were categorized as follows: combination therapy (ETN and MTX started concurrently), step-up therapy (MTX started first and ETN added later), switchers (MTX started and then stopped when or before ETN started), MTX add-on (ETN started first and MTX added later), and ETN only (no MTX use). Data were described using parametric and non-parametric statistics as appropriate. Results Two thousand thirty-two of the five thousand six hundred forty-one patients with JIA met inclusion criteria (74% female, median age at diagnosis 6.0 years [interquartile range 2.0, 11.0]. Most patients (66.9%) were treated with a non-biologic disease modifying anti-rheumatic drug (DMARD), primarily MTX, prior to ETN. There was significant variability in patterns of MTX use prior to starting ETN. Step-up therapy was the most common approach. Only 34.0% of persistent oligoarticular JIA patients continued treatment with a non-biologic DMARD 3 months or more after ETN initiation. ETN persistence overall was 66.3, 49.4, and 37.3% at 24, 36 and 48 months respectively. ETN persistence among spondyloarthritis patients (enthesitis related arthritis and psoriatic JIA) varied by MTX initiation pattern, with higher ETN persistence rates in those who initiated combination therapy (68.9%) and switchers/ETN only (73.3%) patients compared to step-up (65.4%) and MTX add-on (51.1%) therapy. Conclusion This study characterizes contemporary patterns of ETN use in the CARRA Registry. Treatment was largely in keeping with American College of Rheumatology guidelines

Durability of CFRP strands used for prestressing of concrete structural members

This paper presents a comprehensive research conducted to study the synergistic effect of environmental conditions and sustained loading on the mechanical properties of Carbon Fiber Reinforced Polymer (CFRP) prestressing strands. The environmental conditions included exposure of CFRP strands to alkaline solution and sustained loading at an elevated temperature of 55 °C for 3000 and 7000 h. The sustained loading was equivalent to 65 percent of the guaranteed tensile strength of the strands. Mechanical testing performed on the strands included tensile, shear and bond strength as well as evaluation of the elastic modulus of the CFRP strands as affected by the environmental conditions and sustained loading. Durability of the constituent materials of the CFRP strands was also studied