Polycylcic Aromatic Hydrocarbons (PAH's) in dense cloud chemistry

Virtually all detailed gas-phase models of the chemistry of dense interstellar clouds exclude polycyclic aromatic hydrocarbons (PAH's). This omission is unfortunate because from the few studies that have been done on the subject, it is known that the inclusion of PAH's can affect the gas-phase chemistry strongly. We have added PAH's to our network to determine the role they play in the chemistry of cold dense cores. In the models presented here, we include radiative attachment to form PAH-, mutual neutralization between PAH anions and small positively-charged ions, and photodetachment. We also test the sensitivity of our results to changes in the size and abundance of the PAH's. Our results confirm that the inclusion of PAH's changes many of the calculated abundances of smaller species considerably. In TMC-1, the general agreement with observations is significantly improved contrary to L134N. This may indicate a difference in PAH properties between the two regions. With the inclusion of PAH's in dense cloud chemistry, high-metal elemental abundances give a satisfactory agreement with observations. As a result, we do not need to decrease the observed elemental abundances of all metals and we do not need to vary the elemental C/O ratio in order to produce large abundances of carbon species in TMC-1 (CP).Comment: Accepted to ApJ. Astrophysical Journal (2008) accepte

Cholesterol and Lipoprotein Dynamics in a Hibernating Mammal

Hibernating mammals cease feeding during the winter and rely primarily on stored lipids to fuel alternating periods of torpor and arousal. How hibernators manage large fluxes of lipids and sterols over the annual hibernation cycle is poorly understood. The aim of this study was to investigate lipid and cholesterol transport and storage in ground squirrels studied in spring, summer, and several hibernation states. Cholesterol levels in total plasma, HDL and LDL particles were elevated in hibernators compared with spring or summer squirrels. Hibernation increased plasma apolipoprotein A-I expression and HDL particle size. Expression of cholesterol 7 alpha-hydroxylase was 13-fold lower in hibernators than in active season squirrels. Plasma triglycerides were reduced by fasting in spring but not summer squirrels. In hibernators plasma β-hydroxybutyrate was elevated during torpor whereas triglycerides were low relative to normothermic states. We conclude that the switch to a lipid-based metabolism during winter, coupled with reduced capacity to excrete cholesterol creates a closed system in which efficient use of lipoproteins is essential for survival

The ANTENATAL multicentre study to predict postnatal renal outcome in fetuses with posterior urethral valves: objectives and design

Abstract Background Posterior urethral valves (PUV) account for 17% of paediatric end-stage renal disease. A major issue in the management of PUV is prenatal prediction of postnatal renal function. Fetal ultrasound and fetal urine biochemistry are currently employed for this prediction, but clearly lack precision. We previously developed a fetal urine peptide signature that predicted in utero with high precision postnatal renal function in fetuses with PUV. We describe here the objectives and design of the prospective international multicentre ANTENATAL (multicentre validation of a fetal urine peptidome-based classifier to predict postnatal renal function in posterior urethral valves) study, set up to validate this fetal urine peptide signature. Methods Participants will be PUV pregnancies enrolled from 2017 to 2021 and followed up until 2023 in >30 European centres endorsed and supported by European reference networks for rare urological disorders (ERN eUROGEN) and rare kidney diseases (ERN ERKNet). The endpoint will be renal/patient survival at 2 years postnatally. Assuming α = 0.05, 1–β = 0.8 and a mean prevalence of severe renal outcome in PUV individuals of 0.35, 400 patients need to be enrolled to validate the previously reported sensitivity and specificity of the peptide signature. Results In this largest multicentre study of antenatally detected PUV, we anticipate bringing a novel tool to the clinic. Based on urinary peptides and potentially amended in the future with additional omics traits, this tool will be able to precisely quantify postnatal renal survival in PUV pregnancies. The main limitation of the employed approach is the need for specialized equipment. Conclusions Accurate risk assessment in the prenatal period should strongly improve the management of fetuses with PUV

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Agricultural vegetation classification with SVM and polarimetric SAR data

WOSInternational audienc

Sex-dependent association of circulating sex steroids and pituitary hormones with treatment-free survival in chronic lymphocytic leukemia patients

Chronic lymphocytic leukemia (CLL) is not considered a hormone-regulated cancer although sex is a recognized risk factor with men more frequently diagnosed and developing progressive disease. We hypothesized that variable hormonal exposure may have a sexually dimorphic influence on treatment-free survival (TFS). In 156 CLL cases, we quantitatively profiled 29 circulating steroids (progesterone, adrenal precursors, androgens, estrogens, and catechol estrogens) as well as luteinizing hormone (LH) and follicle-stimulating hormone. Median TFS was shorter for men than that for women (80.7 vs. 135.0 months, P =0.033). Circulating hormone profiles in CLL patients were significantly different from those of healthy donors. In male CLL cases, higher LH levels were associated with shorter TFS (adjusted hazard ratio (HRadj) 2.11; P =0.004). In female CLL cases, high levels of the potent androgens testosterone and dihydrotestosterone and the sum of methoxy estrogens were associated with an improved TFS with HRadj values of 0.24 (P =0.007), 0.54 (P =0.023), and 0.31 (P =0.034), respectively. Reduced TFS was observed for women with CLL exhibiting high expression of the steroid-inactivating UGT2B17 enzyme. This study is the first to establish a link between the outcome of CLL patients, sex steroids, and pituitary hormones, revealing a sex-specific hormonal imbalance associated with disease progression.(VLID)359162

Phosphorylation pattern of 5-LO1 and 5-LO∆13 is different in HEK293 cells.

<p>Immunoblot analysis of resting HEK293 cells expressing either 5-LO∆13 or 5-LO∆13. All cells also expressed FLAP and CLP. After separation of proteins by SDS-PAGE, membranes were subject to western blots using anti phospho-serine 523 (S523) or anti-phospho-serine 271 (S271). Expression of 5-LO isoforms was verified by blotting using anti-5-LO (5-LO). The immunoblots show the results of 3 independent experiments.</p

Impact of W102A mutations and of FLAP expression on the biosynthesis of 5-LO products.

<p>HEK293 cells expressing FLAP-HA or not were transfected with expression vectors coding for 5-LO1, the 5-LO1-W102A mutant, 5-LO∆13 or the 5-LO∆13-W102A mutant as shown. Control cells (last column) were transfected with a control pcDNA3.1 vector. HEK293 cells were then stimulated with 1 μM thapsigargin and 10 μM AA. 5-LO products were measured by HPLC as described in the Methods section and represent the sum of LTB₄, its trans isomers and 5-hydroxyeicosatetraenoic acid. Data represent means ± SEM of 3 or 4 independent experiments. *Values without a common superscript are different, p<0.05.</p

The Δ-13 isoform of 5-lipoxygenase inhibits LT biosynthesis in a dose-dependant manner.

<p><b>(A)</b> Immunoblots showing expression of 5-LO1 (top band) and 5-LOΔ13 (lower band) after transfections with the indicated ratios of 5-LOΔ13/5-LO1 expression vectors, as well as the presence of FLAP-HA and β-actin as loading control in HEK293 cells. <b>(B)</b> HEK293 cells expressing FLAP-HA and transfected with the indicated ratios of 5-LO1 and 5-LO∆13 expression vectors were stimulated with 1 μM thapsigargin and 10 μM AA for 30 minutes. 5-LO products were measured by HPLC as described in the Methods section. Leukotrienes (LTs) are the sum of LTB₄ and its trans isomers. 5-HETE = 5-hydroxyeicosatetraenoic acid. <b>(C)</b> HeLa cells transfected with a 1:1 ratio of vectors expressing 5-LO1 and 5-LO∆13 were stimulated under the same conditions as in (B) and LTs and 5-HETE production were measured. Immunoblots are representative of 4 independent experiments. Data represent means ± SEM of 4 independent experiments. *Different from control p<0.05, and **p<0.01.</p

Intensity profiles of of 5-LO1 and 5-LO∆13 staining in resting and stimulated cells.

<p>HEK293 cells expressing FLAP which were transfected to express either 5-LO1 or 5-LO∆13 were stimulated with 1 μM A23187 and 10 μM AA or were incubated with their diluent (resting) for 10 minutes. Cells were then fixed and permeabilized and then incubated with rabbit anti-5-LO. Slides were then incubated with an Alexa488-conjugated secondary anti-rabbit antibody and with DAPI to visualize nuclei, and slides were then mounted. Samples were analysed by confocal microscopy and the intensity of the signals of cross-sections of cells were measured as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132607#pone.0132607.g005" target="_blank">Fig 5</a>. <b>Top panels:</b> The intensity of each cross section was measured at the centre of the nucleus (N), at the nuclear envelope (E) identified by the edge of DAPI staining, at 1 μm and at 3 μm from the nuclear envelope (cytoplasmic side). Values are means ± SEM, n = 9. Values in the same figure without a common superscript are different, p<0.05. <b>Bottom panel:</b> Box and whisker plots showing the distance from the centre of the nucleus of the most intense anti-5-LO staining of cross sections. The box represents the two middle quartiles of data, the vertical line in the box is the median and the whiskers represent the minimum and maximum of all the data. *Median value different from others, p<0.05. Values in all panels are from intensity cross sections of 9 cells per condition from three different fields of view, each field representing a separate experiment.</p