Inhibition of fungal and mammalian sterol biosynthesis by 2-aza-2,3-dihydrosqualene

Abstract2-Aza-2,3-dihydrosqualene (I) and a quaternary ammonium derivative (II) inhibited ergosterol biosynthesis in cells and cell-free extracts of the pathogenic yeast Candida albicans as measured by incorporation of radiolabelled precursors. The compounds inhibited squalene epoxidase and 2,3-oxidosqualene cyclase to varying degrees in microsomes from C. albicans and from rat liver. The rat liver epoxidase was 50% inhibited by I at 2.4 μM. In C. albicans cells, but not in cell-free extracts, I also inhibited lanosterol demethylation and led to accumulation of an unidentified polar product

Differential activation of human skin cells by platelet activating factor: Stimulation of phosphoinositide turnover and arachidonic acid mobilization in keratinocytes but not in fibroblasts

Treatment of cultured adult human keratinocytes with platelet activating factor (PAF) resulted in a rapid, dose dependent accumulation of inositol phosphates. Inositol trisphosphate (IP3), inositol bisphosphate (IP2) and inositol phosphate (IP) were elevated within 15 seconds of exposure to PAF (1[mu]M). Lyso-PAF, phosphatidylcholine (PC) and lyso-PC had no effect on levels of inositol phosphates, indicating that the effect of PAF was specific. PAF also raised cellular 1,2-diacylglycerol content (2-fold) within two minutes of addition and stimulated mobilization of arachidonic acid (AA) and release of prostaglandin E2. In contrast, PAF did not stimulate phosphoinositide turnover or AA release in cultured dermal fibroblasts. These results suggest that the inflammatory effects of PAF in human skin result, at least in part, from its ability to directly activate keratinocytes and stimulate release of pro-inflammatory eicosanoids.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27754/1/0000147.pd

Habitat Characteristics of Bracken-Covered Areas Intended for Afforestation in Ličko Sredogorje

Background and Purpose: Forest cultures in continental part of Croatia are mainly based on bracken-covered areas and moors on deserted agriculture soils and pastures. Successful afforestation i.e. establishment of forest cultures depends among other things on the understanding of habitats and ecology of forest trees. The choice of best species of forest trees for afforestation needs to be based on the research in soil and climate characteristics of target habitats. The aims of this research were to show mesoclimatic characteristics of Ličko sredogorje and microclimatic and pedological characteristics of Ličko polje. Also, based on habitat characteristics and ecology of forest trees, the aim was to determine species of forest trees suitable for afforestation of bracken-covered areas. Materials and Methods: Climate, microclimate, pedological and plant nutrition researches were done at the area of Lika highlands. Climate analysis was done according to air temperatures, amount of precipitation, relative air humidity and other climate elements and appearances. Composite soil samples were taken from the depth of 0-30 cm in order to determine plant nutrition potential. Samples were prepared for further analysis in the laboratory. Results: The highest average annual air temperature of 9.6 °C was found at weather station Gračac and the lowest at Korenica station (8.1 °C). Average amount of precipitation for this region was around 1500 mm. Monthly rain factors were ranging from arid to perhumid. Considering thermal character of the climate, the area has moderately warm climate. Average volumetric soil humidity is 14.2 %. Soil has strong acid reaction, is very humus, good to richly supplied with total nitrogen, content of physiologically active phosphorus and potassium is low, and C/N ration normal. Conclusions: According to habitat characteristics in the area of Ličko sredogorje and ecological demands of forest tree species, forest cultures of Common birch (Betula pendula Roth.), Common spruce (Picea abies Karst.), Eastern white pine (Pinus strubus L.), Black pine (Pinus nigra subsp. austriaca Asch i Gr.), Common pine (Pinus sylvestris L.) and European trembling aspen (Populus tremula L.) can be established

Targeting the live market: recovery of Norway lobsters Nephrops norvegicus (L.) from trawl-capture as assessed by stress-related parameters and nucleotide breakdown

The recovery potential of Norway lobsters (Nephrops norvegicus) held in on-board seawater tanks after trawl-capture was assessed at two different times of the year (winter and summer). Survival recorded 24 h after trawl-capture was 84.83 ± 0.93% in the winter compared to 75.35 ± 2.92% in the summer. Stress-related parameters in the muscle (arginine phosphate, glycogen and L-lactate) and in the haemolymph (L-lactate) were measured, together with nucleotide breakdown products in the muscle (yielding the “Adenylate Energy Charge” or AEC ratio). All parameters analysed were responsive to the stress of the trawl-capture and subsequently recovered towards resting values, but did so at different rates. The fact that some measures recovered at a faster rate than others should be taken into account when trying to develop an index of metabolic stress for this species. Animals trawled in the winter recovered to AEC values above 0.8 within 4 h of placing them in on-board seawater tanks, whereas animals trawled in the summer took 24 h to reach these values. Furthermore, at the end of the trials animals trawled in the summer presented significantly higher haemolymph L-lactate and lower muscle glycogen reserves than the animals trawled in the winter, suggesting a faster recovery in the winter compared to the summer. Finally, animals in the winter were better able to endure further stresses (an emersion of 1 h while animals were transported to the commercial handling facilities). Therefore, as a code of practice it is advised that trawled N. norvegicus directed to the live trade should be allowed to recover for at least 4–6 h in on-board tanks, and extra care should be taken especially in the summer, if further stresses such as additional emersion are to be applied within the first 24 h after capture

Online Small-Sat Knowledge Repositories and Modeling Tools for Risk Reduction and Enhanced Mission Success

Developers of small satellites face the challenges of a short development schedule, incomplete information about parts from vendors, and limited budgets. The situation is complicated by the need to use commercial electronic parts rather than radiation hardened parts to meet performance and budget constraints. Fortunately, a number of organizations are standing up new modeling and data resources that are available for free online. Motivation for sharing models, part data, and lessons learned include shorter development times, increased mission success likelihood, and training the next generation of space professionals. The purpose of this paper is to make these resources and their complementary capabilities known to the small satellite community. Five free online platforms are discussed that address various parts of the information and modeling challenges posed by when electronics are operated in space, especially commercial electronics. The first platform is the Small Satellite Reliability Initiative (SSRI) Knowledge Base, a Wikipedia-like site that documents knowledge useful for successful small satellite missions. The second platform is Radiation Guidelines for Notional Threat Identification and Classification (RGENTIC), which accepts user input on electronic part types and mission parameters, then produces a list of possible radiation concerns for various part-types. The third platform is Systems Engineering Assurance and Modeling (SEAM), which incorporates architectural system modeling for identifying radiation fault propagation, Goal Structuring Notation, a visual argument scheme for creating radiation assurance cases, and construction of fault trees and Bayesian nets for reliability analysis. The fourth platform is the Parts, Materials and Processes Encyclopedia (PMPedia), a repository for information on relevant information for small satellite performance on electronic parts, material properties, and constructing processes. The fifth platform is Cosmic Ray Effects on Microelectronics (CREME), a collection of tools that enable the user to estimate the effect of the cosmic ray environment on various microelectronic parts. Taken together, these tools can significantly improve the chance of mission success

Transient Elastography in Community Alcohol Services: Can It Detect Significant Liver Disease and Impact Drinking Behaviour?

Introduction: Alcohol is the leading cause of cirrhosis in Western populations. The early identification of high-risk drinkers followed by intervention is an effective way to reduce harm. We aim to assess the feasibility of integrating transient elastography (TE) into community alcohol services, and to determine its impact on modifying drinking behaviours. Method: A prospective cohort study was conducted at a community alcohol clinic in Nottingham, UK (April 2012 to March 2014). Patients (>18 years) with a primary alcohol problem were recruited. Those known to liver services or those known to have chronic liver disease were excluded. Significant liver fibrosis was defined by a liver stiffness of >8 kilopascal (kPa). Follow-up was for a minimum of six months. Data were descriptively analysed for significant differences between patients with a normal liver stiffness versus raised liver stiffness. Results: 156 patients were invited; n = 87 attended and n = 86 underwent successful TE. The majority were male (n = 53, 70.0%), and the mean age was 46.3 years (SD ± 9.8). Median liver stiffness was 6.9 kPa (range 3.1–75.0kPa). Clinically significant liver fibrosis was identified in n = 33 (38.4%), of which n = 6 were in the cirrhotic range (≥15 kPa). The baseline median self-reported alcohol intake for normal stiffness was 126 units per week (range 24–378) and in raised stiffness was 149.0 units per week (range 39.0–420.0); this difference was nonsignificant (p = 0.338). The median reduction in self-reported alcohol intake in the whole cohort was 65.0 units per week (range 27.0–88.0, p < 0.001); in the normal liver stiffness group it was 25.0 units per week (range 18.0–75.0, p = 0.154), and in the raised liver stiffness group it was 78.5 units per week (range 36.0–126.0, p < 0.001). Conclusion: The study demonstrated that transient elastography is a feasible tool to stratify clinically significant liver disease in community alcohol services. It can stimulate a change in high-risk drinking behaviour and a normal liver stiffness result does not provide false reassurance to participants

Targeting of Slc25a21 is associated with orofacial defects and otitis media due to disrupted expression of a neighbouring gene.

Homozygosity for Slc25a21(tm1a(KOMP)Wtsi) results in mice exhibiting orofacial abnormalities, alterations in carpal and rugae structures, hearing impairment and inflammation in the middle ear. In humans it has been hypothesised that the 2-oxoadipate mitochondrial carrier coded by SLC25A21 may be involved in the disease 2-oxoadipate acidaemia. Unexpectedly, no 2-oxoadipate acidaemia-like symptoms were observed in animals homozygous for Slc25a21(tm1a(KOMP)Wtsi) despite confirmation that this allele reduces Slc25a21 expression by 71.3%. To study the complete knockout, an allelic series was generated using the loxP and FRT sites typical of a Knockout Mouse Project allele. After removal of the critical exon and neomycin selection cassette, Slc25a21 knockout mice homozygous for the Slc25a21(tm1b(KOMP)Wtsi) and Slc25a21(tm1d(KOMP)Wtsi) alleles were phenotypically indistinguishable from wild-type. This led us to explore the genomic environment of Slc25a21 and to discover that expression of Pax9, located 3' of the target gene, was reduced in homozygous Slc25a21(tm1a(KOMP)Wtsi) mice. We hypothesize that the presence of the selection cassette is the cause of the down regulation of Pax9 observed. The phenotypes we observed in homozygous Slc25a21(tm1a(KOMP)Wtsi) mice were broadly consistent with a hypomorphic Pax9 allele with the exception of otitis media and hearing impairment which may be a novel consequence of Pax9 down regulation. We explore the ramifications associated with this particular targeted mutation and emphasise the need to interpret phenotypes taking into consideration all potential underlying genetic mechanisms

Software Citation Checklist for Developers

This document provides a minimal, generic checklist that developers of software (either open or closed source) used in research can use to ensure they are following good practice around software citation. This will help developers get credit for the software they create, and improve transparency, reproducibility, and reuse