Assessment of the effect of esterified propoxylated glycerol (EPG) on the status of fat-soluble vitamins and select water-soluble nutrients following dietary administration to humans for 8weeks

AbstractThis double-blind, randomized, controlled study assessed the effect of esterified propoxylated glycerol (EPG) on fat-soluble vitamins and select nutrients in human subjects. For 8weeks, 139 healthy volunteers consumed a core diet providing adequate caloric and nutrient intakes. The diet included items (spread, muffins, cookies, and biscuits) providing EPG (10, 25, and 40g/day) vs. margarine alone (control). EPG did not significantly affect circulating retinol, α-tocopherol, or 25-OH D2, but circulating β-carotene and phylloquinone were lower in the EPG groups, and PIVKA-II levels were higher; 25-OH D3 increased but to a lesser extent than the control. The effect might be related to EPG acting as a lipid “sink” during gastrointestinal transit. No effects were seen in secondary endpoint measures (physical exam, clinical pathology, serum folate, RBC folate, vitamin B12, zinc, iron, calcium, phosphorus, osteocalcin, RBP, intact PTH, PT, PTT, cholesterol, HDL-C, LDL-C, triglycerides). Gastrointestinal adverse events (gas with discharge; diarrhea; oily spotting; oily evacuation; oily stool; liquid stool; soft stool) were reported more frequently by subjects receiving 25 or 40g/day of EPG. In general, the incidence and duration of these symptoms correlated directly with EPG dietary concentration. The results suggest 10g/day of EPG was reasonably well tolerated

Inhibiting ERK Activation with CI-1040 Leads to Compensatory Upregulation of Alternate MAPKs and Plasminogen Activator Inhibitor-1 following Subtotal Nephrectomy with No Impact on Kidney Fibrosis

Extracellular-signal regulated kinase (ERK) activation by MEK plays a key role in many of the cellular processes that underlie progressive kidney fibrosis including cell proliferation, apoptosis and transforming growth factor β1-mediated epithelial to mesenchymal transition. We therefore assessed the therapeutic impact of ERK1/2 inhibition using a MEK inhibitor in the rat 5/6 subtotal nephrectomy (SNx) model of kidney fibrosis. There was a twentyfold upregulation in phospho-ERK1/2 expression in the kidney after SNx in Male Wistar rats. Rats undergoing SNx became hypertensive, proteinuric and developed progressive kidney failure with reduced creatinine clearance. Treatment with the MEK inhibitor, CI-1040 abolished phospho- ERK1/2 expression in kidney tissue and prevented phospho-ERK1/2 expression in peripheral lymphocytes during the entire course of therapy. CI-1040 had no impact on creatinine clearance, proteinuria, glomerular and tubular fibrosis, and α-smooth muscle actin expression. However, inhibition of ERK1/2 activation led to significant compensatory upregulation of the MAP kinases, p38 and JNK in kidney tissue. CI-1040 also increased the expression of plasminogen activator inhibitor-1 (PAI-1), a key inhibitor of plasmin-dependent matrix metalloproteinases. Thus inhibition of ERK1/2 activation has no therapeutic effect on kidney fibrosis in SNx possibly due to increased compensatory activation of the p38 and JNK signalling pathways with subsequent upregulation of PAI-1

Nanoscale probing of electron-regulated structural transitions in silk proteins by near-field IR imaging and nano-spectroscopy

Silk protein fibres produced by silkworms and spiders are renowned for their unparalleled mechanical strength and extensibility arising from their high-β-sheet crystal contents as natural materials. Investigation of β-sheet-oriented conformational transitions in silk proteins at the nanoscale remains a challenge using conventional imaging techniques given their limitations in chemical sensitivity or limited spatial resolution. Here, we report on electron-regulated nanoscale polymorphic transitions in silk proteins revealed by near-field infrared imaging and nano-spectroscopy at resolutions approaching the molecular level. The ability to locally probe nanoscale protein structural transitions combined with nanometre-precision electron-beam lithography offers us the capability to finely control the structure of silk proteins in two and three dimensions. Our work paves the way for unlocking essential nanoscopic protein structures and critical conditions for electron-induced conformational transitions, offering new rules to design protein-based nanoarchitectures.National Science Foundation (U.S.) (1563422)National Science Foundation (U.S.) (1562915

Clinical impairment in premanifest and early Huntington's disease is associated with regionally specific atrophy.

TRACK-HD is a multicentre longitudinal observational study investigating the use of clinical assessments and 3-Tesla magnetic resonance imaging as potential biomarkers for future therapeutic trials in Huntington's disease (HD). The cross-sectional data from this large well-characterized dataset provide the opportunity to improve our knowledge of how the underlying neuropathology of HD may contribute to the clinical manifestations of the disease across the spectrum of premanifest (PreHD) and early HD. Two hundred and thirty nine gene-positive subjects (120 PreHD and 119 early HD) from the TRACK-HD study were included. Using voxel-based morphometry (VBM), grey and white matter volumes were correlated with performance in four domains: quantitative motor (tongue force, metronome tapping, and gait); oculomotor [anti-saccade error rate (ASE)]; cognition (negative emotion recognition, spot the change and the University of Pennsylvania smell identification test) and neuropsychiatric measures (apathy, affect and irritability). After adjusting for estimated disease severity, regionally specific associations between structural loss and task performance were found (familywise error corrected, P < 0.05); impairment in tongue force, metronome tapping and ASE were all associated with striatal loss. Additionally, tongue force deficits and ASE were associated with volume reduction in the occipital lobe. Impaired recognition of negative emotions was associated with volumetric reductions in the precuneus and cuneus. Our study reveals specific associations between atrophy and decline in a range of clinical modalities, demonstrating the utility of VBM correlation analysis for investigating these relationships in HD

“Dogged” Search of Fresh Nakhla Surfaces Reveals New Alteration Textures

Special Issue: 74th Annual Meeting of the Meteoritical Society, August 8-12, 2011, London, U.K.International audienceCarbonaceous chondrites are considered as amongst the most primitive Solar System samples available. One of their primitive characteristics is their enrichment in volatile elements.This includes hydrogen, which is present in hydrated and hydroxylated minerals. More precisely, the mineralogy is expected to be dominated by phyllosilicates in the case of CM chondrites, and by Montmorillonite type clays in the case of CI. Here, in order to characterize and quantify the abundance of lowtemperature minerals in carbonaceous chondrites, we performed thermogravimetric analysis of matrix fragments of Tagish Lake, Murchison and Orgueil

Constraining the Origin of Impact Craters on Al Foils from the Stardust Interstellar Dust Collector

Preliminary examination (PE) of the aerogel tiles and Al foils from the Stardust Interstellar Dust Collector has revealed multiple impact features. Some are most likely due to primary impacts of interstellar dust (ISD) grains, and others are associated with secondary impacts of spacecraft debris, and possibly primary impacts of interplanetary dust particles (IDPs) [1, 2]. The current focus of the PE effort is on constraining the origin of the individual impact features so that definitive results from the first direct laboratory analysis of contemporary ISD can be reported. Because crater morphology depends on impacting particle shape and composition, in addition to the angle and direction of impact, unique particle trajectories are not easily determined. However, elemental analysis of the crater residues can distinguish real cosmic dust from the spacecraft debris, due to the low cosmic abundance of many of the elements in the spacecraft materials. We present here results from the elemental analysis of 24 craters and discuss the possible origins of 4 that are identified as candidate ISD impact

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Performance and Operation of the CMS Electromagnetic Calorimeter

The operation and general performance of the CMS electromagnetic calorimeter using cosmic-ray muons are described. These muons were recorded after the closure of the CMS detector in late 2008. The calorimeter is made of lead tungstate crystals and the overall status of the 75848 channels corresponding to the barrel and endcap detectors is reported. The stability of crucial operational parameters, such as high voltage, temperature and electronic noise, is summarised and the performance of the light monitoring system is presented

Heterologous Expression of Membrane Proteins: Choosing the Appropriate Host

International audienceBACKGROUND: Membrane proteins are the targets of 50% of drugs, although they only represent 1% of total cellular proteins. The first major bottleneck on the route to their functional and structural characterisation is their overexpression; and simply choosing the right system can involve many months of trial and error. This work is intended as a guide to where to start when faced with heterologous expression of a membrane protein. METHODOLOGY/PRINCIPAL FINDINGS: The expression of 20 membrane proteins, both peripheral and integral, in three prokaryotic (E. coli, L. lactis, R. sphaeroides) and three eukaryotic (A. thaliana, N. benthamiana, Sf9 insect cells) hosts was tested. The proteins tested were of various origins (bacteria, plants and mammals), functions (transporters, receptors, enzymes) and topologies (between 0 and 13 transmembrane segments). The Gateway system was used to clone all 20 genes into appropriate vectors for the hosts to be tested. Culture conditions were optimised for each host, and specific strategies were tested, such as the use of Mistic fusions in E. coli. 17 of the 20 proteins were produced at adequate yields for functional and, in some cases, structural studies. We have formulated general recommendations to assist with choosing an appropriate system based on our observations of protein behaviour in the different hosts. CONCLUSIONS/SIGNIFICANCE: Most of the methods presented here can be quite easily implemented in other laboratories. The results highlight certain factors that should be considered when selecting an expression host. The decision aide provided should help both newcomers and old-hands to select the best system for their favourite membrane protein

Microanalysis of Hypervelocity Impact Residues of Possible Interstellar Origin

The NASA Stardust spacecraft deployed two collector trays, one dedicated to the collection of dust from Comet Wild 2, and the other for the capture of interstellar dust (ISD). The samples were returned successfully to Earth in 2006, and now provide an unprecedented opportunity for laboratory-based microanalysis of materials from the outer solar system and beyond. Results from the cometary sample studies have demonstrated that Wild 2 contains much more refractory condensate material and much less pristine extra-solar material than expected, which further indicates that there was significant transport of inner solar system materials to the Kuiper Belt in the early solar system [1]. The analysis of the interstellar samples is still in the preliminary examination (PE) phase, due to the level of difficulty in the definitive identification of the ISD features, the overall low abundance, and its irreplaceable nature, which necessitates minimally invasive measurements [2]. We present here coordinated microanalysis of the impact features on the Al foils, which have led to the identification of four impacts that are possibly attributable to interstellar dust. Results from the study of four ISD candidates captured in aerogel are presented elsewhere [2]