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Background: Heterozygous loss-of-function mutations in the synaptic scaffolding gene SHANK2 are strongly associated with autism spectrum disorder (ASD). However, their impact on the function of human neurons is unknown. Derivation of induced pluripotent stem cells (iPSC) from affected individuals permits generation of live neurons to answer this question. Methods: We generated iPSCs by reprogramming dermal fibroblasts of neurotypic and ASD-affected donors. To isolate the effect of SHANK2, we used CRISPR/Cas9 to knock out SHANK2 in control iPSCs and correct a heterozygous nonsense mutation in ASD-affected donor iPSCs. We then derived cortical neurons from SOX1+ neural precursor cells differentiated from these iPSCs. Using a novel assay that overcomes line-to-line variability, we compared neuronal morphology, total synapse number, and electrophysiological properties between SHANK2 mutants and controls. Results: Relative to controls, SHANK2 mutant neurons have increased dendrite complexity, dendrite length, total synapse number (1.5-2-fold), and spontaneous excitatory postsynaptic current (sEPSC) frequency (3-7.6-fold). Conclusions: ASD-associated heterozygous loss-of-function mutations in SHANK2 increase synaptic connectivity among human neurons by increasing synapse number and sEPSC frequency. This is partially supported by increased dendrite length and complexity, providing evidence that SHANK2 functions as a suppressor of dendrite branching during neurodevelopment.
The final stages of low-mass stellar evolution are characterized by significant mass loss due to stellar pulsations during the AGB phase, which lead to the development of planetary nebulae. Molecular masers of H2O, SiO, and ground state OH transitions are commonly detected in oxygen-rich late-type stars (OH/IR objects). In contrast, excited OH maser transitions are rare. We discuss our study of the carbon-rich pre-planetary nebula CRL618 (a prototypical post-AGB star). Observations conducted in May 2008 with the 305m Arecibo Telescope resulted in the first detection of a 4765MHz OH maser line in a late-type stellar object; the detection was confirmed a few months later also with Arecibo. Subsequent observations in 2015 and 2017 resulted in non-detection of the 4765MHz OH line. Our observations indicate that the 4765MHz OH maser in CRL 618 is highly variable, possibly tracing a short-lived phenomenon during the development of a pre-planetary nebula.
Introduction: Point of care ultrasound (PoCUS) provides invaluable information during resuscitation efforts in cardiac arrest by determining presence/absence of cardiac activity and identifying reversible causes such as pericardial tamponade. There is no agreed guideline on how to safely and effectively incorporate PoCUS into the advanced cardiac life support (ACLS) algorithm. We consider that a consensus-based priority checklist using a “4 F’s” approach (Fluid; Form; Function; Filling), would provide a better algorithm during ACLS. Methods: The ultrasound subcommittee of the Australasian College for Emergency Medicine (ACEM) drafted a checklist incorporating PoCUS into the ACLS algorithm. This was further developed using the input of 24 international experts associated with five professional organizations led by the International Federation of Emergency Medicine. A modified Delphi tool was developed to reach an international consensus on how to integrate ultrasound into cardiac arrest algorithms for emergency department patients. Results: Consensus was reached following 3 rounds. The agreed protocol focuses on the timing of PoCUS as well as the specific clinical questions. Core cardiac windows performed during the rhythm check pause in chest compressions are the sub-xiphoid and parasternal cardiac views. Either view should be used to detect pericardial fluid, as well as examining ventricular form (e.g. right heart strain) and function, (e.g. asystole versus organized cardiac activity). Supplementary views include lung views (for absent lung sliding in pneumothorax and for pleural fluid), and IVC views for filling. Additional ultrasound applications are for endotracheal tube confirmation, proximal leg veins for DVT, or for sources of blood loss (AAA, peritoneal/pelvic fluid). Conclusion: The authors hope that this process will lead to a consensus-based SHoC-cardiac arrest guideline on incorporating PoCUS into the ACLS algorithm.
Periods of rapid growth seen during the early stages of fetal development, including cell proliferation and differentiation, are greatly influenced by the maternal environment. We demonstrate here that over-nutrition, specifically exposure to a high-fat diet in utero, programed the extent of atherosclerosis in the offspring of ApoE*3 Leiden transgenic mice. Pregnant ApoE*3 Leiden mice were fed either a control chow diet (2.8% fat, n=12) or a high-fat, moderate-cholesterol diet (MHF, 19.4% fat, n=12). Dams were fed the chow diet during the suckling period. At 28 days postnatal age wild type and ApoE*3 Leiden offspring from chow or MHF-fed mothers were fed either a control chow diet (n=37) or a diet rich in cocoa butter (15%) and cholesterol (0.25%), for 14 weeks to induce atherosclerosis (n=36). Offspring from MHF-fed mothers had 1.9-fold larger atherosclerotic lesions (P<0.001). There was no direct effect of prenatal diet on plasma triglycerides or cholesterol; however, transgenic ApoE*3 Leiden offspring displayed raised cholesterol when on an atherogenic diet compared with wild-type controls (P=0.031). Lesion size was correlated with plasma lipid parameters after adjustment for genotype, maternal diet and postnatal diet (R2=0.563, P<0.001). ApoE*3 Leiden mothers fed a MHF diet developed hypercholesterolemia (plasma cholesterol two-fold higher than in chow-fed mothers, P=0.011). The data strongly suggest that maternal hypercholesterolemia programs later susceptibility to atherosclerosis. This is consistent with previous observations in humans and animal models.
The compact steep spectrum (CSS) and gigahertz peaked spectrum (GPS) sources are widely believed to be young radio sources, with ages ≤106 yr. If the activity in the nucleus is fuelled by the supply of gas, one might find evidence of this gas by studying the structural and polarisation characteristics of CSS sources and their evolution through this gas. In this paper we discuss some of the possible ‘smoking-gun’ evidence of this gas which may have triggered and fuelled the radio source.
In this article, Ontario's stroke rehabilitation system is used to exemplify the challenges faced by rehabilitation and healthcare systems across Canada who are attempting to provide quality care to patients in the face of increasing demands. Currently, Ontario's rehabilitation system struggles in its efforts to provide accessible and comprehensive care to patients recovering from stroke. We begin our exploration by identifying both the primary stakeholders and the underlying factors that have contributed to the current challenges. The framework put forward in the Canadian Medical Association's recommendations for transformation is then used to suggest a vision for a more patient-focused system incorporating three key principles: a broader perspective, a patient-first approach, and greater unity. The use of health information technology, proper incentives, and greater accountability are discussed as mechanisms to improve the quality and efficiency of care.
Dietary conjugated linoleic acids (CLA) have been reported to have a number of isomer-dependent effects on lipid metabolism including reduction in adipose tissue deposition, changes in plasma lipoprotein concentrations and hepatic lipid accumulation. The aim of this study was to compare the effect of individual CLA isomers against lipogenic and high ‘Western’ fat background diets. Golden Syrian hamsters were fed a high-carbohydrate rodent chow or chow supplemented with 17·25 % fat formulated to represent the type and amount of fatty acids found in a typical ‘Western’ diet (including 0·2 % cholesterol). Diets were further supplemented with 0·25 % (w/w) rapeseed oil, cis9, trans11 (c9,t11)-CLA or trans10, cis12 (t10,c12)-CLA. Neither isomer had a significant impact on plasma lipid or lipoprotein concentrations. The t10,c12-CLA isomer significantly reduced perirenal adipose tissue depot mass. While adipose tissue acetyl CoA carboxylase and fatty acid synthase mRNA concentrations (as measured by quantitative PCR) were unaffected by CLA, lipoprotein lipase mRNA was specifically reduced by t10,c12-CLA, on both background diets (P < 0·001). This was associated with a specific reduction of sterol regulatory element binding protein 1c expression in perirenal adipose tissue (P = 0·018). The isomers appear to have divergent effects on liver TAG content with c9,t11-CLA producing lower concentrations than t10,c12-CLA. We conclude that t10,c12-CLA modestly reduces adipose tissue deposition in the Golden Syrian hamster independently of background diet and this may possibly result from reduced uptake of lipoprotein fatty acids, as a consequence of reduced lipoprotein lipase gene expression.
Lameness in adult ewes can result in reduced prolificacy, lower milk yields and a reduced wool yield (Anon, 1992) and a report by DEFRA (2003) showed 90% of sheep farms had lameness problems. The profiles of fatty acids found in claw lipids from lame cattle have been shown to be different to those in sound animals (Offer et al. 2000). Although the underlying mechanism behind this remains unclear, this offers the possibility of influencing the degree of lameness by manipulating claw lipid composition (Offer et al. 2000). Inoue et al. (1986) have shown that human epidermis with higher levels of lipid also has higher moisture content and bound water content. As water is known to modulate the mechanical properties of claw horn (Baillie et al. 2000), it may be postulated that a change in lipid content through supplementation may allow manipulation of the biomechanical properties of the claw. This may be important in lameness where brittle claw horn is manifest. This study investigates whether a dietary lipid supplement, protected against rumen fermentation, may be a useful tool in controlling the properties of the sheep claw.
Adipose tissue becomes more saturated and less unsaturated with age (Kemp et al., 1981). Desaturation of stearic acid to the oleic acid is catalysed by stearoyl-CoA desaturase (SCD) and increasing the degree of desaturation of lamb is likely to be beneficial in terms of human nutrition. By altering the levels of ovine SCD mRNA, the supply of oleic acid to the tissue could be manipulated, resulting in a practical method of changing the fatty acid profile of the animals meat. Previous work in our laboratory has shown variability between adipose tissue depots in their expression of SCD and that this variability is associated with changes in oleic acid content (Daniel et al, 2004). Such differences in SCD expression between depots implies that there may be even larger variation in SCD expression between breeds. A sheep breed with particularly high level of SCD mRNA could then be exploited through breeding programmes to produce animals with increased desaturase activity and therefore increased oleic acid content. Three sheep breeds, Texel, Beulah and Soay, were therefore used to study the influence of breed and age on SCD expression.
Recent research has focused on a component of ruminant fat, conjugated linoleic acids (CLA), which have been implicated with numerous health promoting properties including anti-carcinogenicity (Belury, 1995). Dietary supplementation with CLA has been shown to have a marked effect on tissue composition in several species, although there is apparently no evidence of such effects being seen in sheep (see Salter et al., 2002). Consequently, the aim of this study was to examine the effect of feeding growing lambs a CLA supplement, protected from rumen degradation, on carcass characteristics and tissue CLA content.
Work was undertaken in 1997 as part of a UK government programme to monitor air quality in the Cornish china clay area. These studies showed that concentrations of airborne particulate matter with an aerodynamic diameter <10 μm (PM10) did not exceed UK National Air Quality Strategy (NAQS, 1995) guidelines but were, however, greater than those normally associated with rural areas. Subsequently, in the summer of 2000, airborne dust sampling was conducted at three sites around the IMERYS (formerly ECCI) Kernick mica dam, a potential source of resuspended airborne particulates from china clay waste minerals. Analytical scanning electron microscopy examination of the collected material suggested that up to 61% of the airborne PM10 monitored next to the mica dam could be associated with china clay extraction compared with 46% 2 km to the south. Results showed the presence of substantial percentages of respirable kaolinite, muscovite and quartz; the major components of china clay waste. The health effects of the particular mineral dust emissions associated with china clay mining are reviewed.
The work described was carried out to study the expression of insulin-like growth factor 1 (IGF-1) and growth hormone-receptor (GHR) mRNA in liver, skeletal muscle and adipose tissue from three breeds of pig with varying growth characteristics. The three breeds studied were the Large Wlrite, noted for its lean tissue; the Duroc, characterized by its high intramuscular fat content; and the Meishan × Landrace (0·5 Meishan), noted for its fat, poorly conformed carcass and slower growth rate. The probes used were designed to monitor promoter usage for IGF-1 expression and also expression of the extra-cellular domain of the GHR. Eighteen gilts, six of each breed, were given a barley/wheat diet (158 g crude protein, 10·7 g lysine and 13·9 MJ energy per kg), to appetite, for 1 to 2 weeks until they reached about 85 kg. Samples of liver, longissimu s dorsi (LD) muscle and three adipose tissue depots (subcutaneous (SC), perirenal (PR) and omental (OM)) were collected immediately after slaughter and frozen in liquid nitrogen (total time of sample collection to plunging of sample into liquid nitrogen was <3 min), prior to extraction of total RNA and ribonuclease protection assays. Individual serum samples collected at exsanguination were frozen prior to IGF-1 radioimmunoassay. There were no breed differences in the serum IGF-1 concentrations (range 49 to 134 μg/l), or in expression of the GHR gene or either class of IGF-1 transcript in the liver. However, there was a significant difference between the breeds in expression of IGF-1 mRNA in the LD muscle (P < 0·001), the order being Duroc > Wliite > Meishan, with only class 1 transcripts of IGF-1 being found. GHR expression in LD muscle was lower in White than in the other tivo breeds (P = 0·022). There was a significant difference between the breeds in expression of IGF-1 mRNA (only class 1 transcripts present) in the adipose tissue (P = 0-006), the order being Wliite · Duroc · Meishan, and also a significant depot difference, with expression being highest in the SC depot (P < 0·001). There were no differences between the breeds or depots in expression of GHR mRNA in adipose tissue. The observed differences in muscle and adipose tissue IGF-1 expression may relate to the overall growth of the animal.
An innovative EBS design of sand-gravel layers for waste disposal under partially saturated conditions is described. Advantages of this EBS are 1) as a hydraulic barrier to advective inflow from the surrounding rock, and 2) as a diffusion barrier to the transport of dissolved or colloidal radionuclides. This sand-gravel barrier design for unsaturated sites is analogous to EBS designs using compacted bentonite backfills/buffers in saturated repository sites. Percolation box experiments, field tests, and natural analogues supporting the advantageous performance of this flow-diversion design are described and estimates for source-term release are calculated.
Small-scale rescue excavations at Llwyn Bryn-dinas hillfort, on the Welsh Borderland, showed that the earliest fortification belonged to the late Bronze Age, with radiocarbon dates in the late 9th and 8th centuries be. A terrace, subsequently cut into the rear of the rampart to accommodate a metal-working floor, was associated with a radiocarbon date centred in the late 3rd century bc. Detailed analysis of the metal-working debris suggests that copper-alloy casting, iron forging and possibly bronze production were carried out within a single workshop. The finds include a distinctive form of handled crucible. The industry appears to have been fairly small-scale, of short duration, and probably only designed to meet the internal needs of the hillfort population. The excavation adds significantly to the local evidence for metal-working during the later prehistoric period. A distinctive zinc-impurity pattern in the copper alloy and raw copper, previously identified in material from other sites nearby, confirms the suggestion of an Iron Age bronze-working industry based on a specific metal source in the north Powys area. In addition, analysis of the iron-working debris suggests the exploitation of a distinctive local ore body. The metal-working activity appears to have come to an abrupt end, possibly with the enlargement or local repair of the rampart. Later phases of activity include a final occupation deposit with an associated radiocarbon date centred in the mid 2nd century bc.
As the first part of a program to investigate the thermal emission of dust at millimeter wavelengths, we present maps of the continuum emission from radio-bright HII regions. These maps have been made with a filled aperture telescope, the NRAO 12-m telescope at Kitt Peak, with a HPBW of 70 arc seconds at 3.5 mm. We used a switched dual-beam technique and a restoration algorithm developed by Emerson et al. (1979 Astron. Ap. 76, 92). We compare these maps with maps made at centimeter wavelengths.
Two experiments were carried out to study the effects of five agronomic variables on the marketable yield of transplanted leeks. In the first experiment two cultivars were used, cvs Splendid and Winterreuzen, and the treatments compared three plantraising systems, two ages of transplant when planted, and two plant population densities, two row spacings and two levels of nitrogen nutrition in the field. In this experiment some treatment interactions were confounded with each other.
In the later experiment only cv. Splendid was grown. There were two plant-raising systems, two plant-raising temperatures, two plant-raising nutrition levels, two times of transplanting (63 or 84 days from sowing) and four different sowings (7 and 28 February, 20 March and 10 April 1984). The duration of the growth period in the field was standardized by harvesting each treatment combination on two occasions, 168 and 189 days after transplanting.
The results from the first experiment showed that plants raised in modules at high temperature, planted early at a high plant density with higher than normal levels of nitrogen gave high marketable (> 12·5 mm in diameter) yields of 7·31 kg/m2, greater than that from any other treatment combination. The second experiment confirmed these general trends but also showed that the date of transplanting was of critical importance with the earliest plantings in the year giving the highest yields and with later plantings resulting in progressively lower yields irrespective of the way in which the transplants were raised. Comparisons with meteorological data showed that decreasing yields were associated with decreasing values of accumulated solar radiation and accumulated day-degrees during field growth.
These results are discussed in relation to other published data. They do not support some of the current recommendations for growing the crop but suggest that much more work needs to be done on production systems for this crop because of the potential for increasing marketable yields.
Intercropping Brussels sprouts with cabbage was studied in two experiments comparing four different intercropping systems with sole crop production. Intercropping presented no agronomic or management problems because both crops had compatible cultural and crop protection requirements. Analysis of Land Equivalent Ratios and Relative Value Totals showed that the four intercropping systems gave consistently larger yields than the sole crops. In one experiment profitability, measured by the gross margin, was higher from all of the intercropping systems and costs per unit of produce were reduced. Similar results were obtained with one intercropping system in the other experiment. Alternative methods of evaluating the results in economic terms are discussed, together with the implications of intercropping in high-input systems of vegetable production.
Conversion of slow scan signals with a continuously updated image display or video recording at TV rate is one of the functions available using a digital video framestore system in conjunction with a scanning electron microscope (SEM, STEM, AEM etc.) or other types of electron probe equipment e.g. EPMA, AES etc. Acceptable inputs are standard TV format; digital sampling of a range of analogue slow scans or directly coupled digital scans.
Routines for noise reduction by spatially resolved time averaging during acquisition are under software control with direct operator involvement in selecting the appropriate conditions via a soft-key redesignation of the VDU numeric pad functions (Fig.l) and within the possibilities of the hardware; making TV rate more useable e.g. to reduce specimen charging and as an essential prerequisite to more sophisticated signal/image processing. Both running average (RVP, 8-bit) and straight integration (16-bit) modes are possible with the Microconsultants Intellect systems in use in our laboratory.