Glucocorticoid-regulated localization of cell surface glycoproteins in rat hepatoma cells is mediated within the Golgi complex.

Glucocorticoid hormones regulate the post-translational maturation and sorting of cell surface and extracellular mouse mammary tumor virus (MMTV) glycoproteins in M1.54 cells, a stably infected rat hepatoma cell line. Exposure to monensin significantly reduced the proteolytic maturation and externalization of viral glycoproteins resulting in a stable cellular accumulation of a single 70,000-Mr glycosylated polyprotein (designated gp70). Cell surface- and intracellular-specific immunoprecipitations of monensin-treated cells revealed that gp70 can be localized to the cell surface only in the presence of 1 microM dexamethasone, while in uninduced cells gp70 is irreversibly sequestered in an intracellular compartment. Analysis of oligosaccharide processing kinetics demonstrated that gp70 acquired resistance to endoglycosidase H with a half-time of 65 min in the presence or absence of hormone. In contrast, gp70 was inefficiently galactosylated after a 60-min lag in uninduced cells while rapidly acquiring this carbohydrate modification in the presence of dexamethasone. Furthermore, in the absence or presence of monensin, MMTV glycoproteins failed to be galactosylated in hormone-induced CR4 cells, a complement-selected sorting variant defective in the glucocorticoid-regulated compartmentalization of viral glycoproteins to the cell surface. Since dexamethasone had no apparent global effects on organelle morphology or production of total cell surface-galactosylated species, we conclude that glucocorticoids induce the localization of cell surface MMTV glycoproteins by regulating a highly selective step within the Golgi apparatus after the acquisition of endoglycosidase H-resistant oligosaccharide side chains but before or at the site of galactose attachment

Glucocorticoid-regulated localization of cell surface glycoproteins in rat hepatoma cells is mediated within the Golgi complex.

Glucocorticoid hormones regulate the post-translational maturation and sorting of cell surface and extracellular mouse mammary tumor virus (MMTV) glycoproteins in M1.54 cells, a stably infected rat hepatoma cell line. Exposure to monensin significantly reduced the proteolytic maturation and externalization of viral glycoproteins resulting in a stable cellular accumulation of a single 70,000-Mr glycosylated polyprotein (designated gp70). Cell surface- and intracellular-specific immunoprecipitations of monensin-treated cells revealed that gp70 can be localized to the cell surface only in the presence of 1 microM dexamethasone, while in uninduced cells gp70 is irreversibly sequestered in an intracellular compartment. Analysis of oligosaccharide processing kinetics demonstrated that gp70 acquired resistance to endoglycosidase H with a half-time of 65 min in the presence or absence of hormone. In contrast, gp70 was inefficiently galactosylated after a 60-min lag in uninduced cells while rapidly acquiring this carbohydrate modification in the presence of dexamethasone. Furthermore, in the absence or presence of monensin, MMTV glycoproteins failed to be galactosylated in hormone-induced CR4 cells, a complement-selected sorting variant defective in the glucocorticoid-regulated compartmentalization of viral glycoproteins to the cell surface. Since dexamethasone had no apparent global effects on organelle morphology or production of total cell surface-galactosylated species, we conclude that glucocorticoids induce the localization of cell surface MMTV glycoproteins by regulating a highly selective step within the Golgi apparatus after the acquisition of endoglycosidase H-resistant oligosaccharide side chains but before or at the site of galactose attachment

Directed paths on hierarchical lattices with random sign weights

We study sums of directed paths on a hierarchical lattice where each bond has either a positive or negative sign with a probability $p$. Such path sums $J$ have been used to model interference effects by hopping electrons in the strongly localized regime. The advantage of hierarchical lattices is that they include path crossings, ignored by mean field approaches, while still permitting analytical treatment. Here, we perform a scaling analysis of the controversial ``sign transition'' using Monte Carlo sampling, and conclude that the transition exists and is second order. Furthermore, we make use of exact moment recursion relations to find that the moments always determine, uniquely, the probability distribution $P(J)$. We also derive, exactly, the moment behavior as a function of $p$ in the thermodynamic limit. Extrapolations ($n\to 0$) to obtain for odd and even moments yield a new signal for the transition that coincides with Monte Carlo simulations. Analysis of high moments yield interesting ``solitonic'' structures that propagate as a function of $p$. Finally, we derive the exact probability distribution for path sums $J$ up to length L=64 for all sign probabilities.Comment: 20 pages, 12 figure

Safety, Immunogenicity and Duration of Protection of the RTS,S/AS02D Malaria Vaccine: One Year Follow-Up of a Randomized Controlled Phase I/IIb Trial

The RTS,S/AS02(D) vaccine has been shown to have a promising safety profile, to be immunogenic and to confer protection against malaria in children and infants.We did a randomized, controlled, phase I/IIb trial of RTS,S/AS02(D) given at 10, 14 and 18 weeks of age staggered with routine immunization vaccines in 214 Mozambican infants. The study was double-blind until the young child completed 6 months of follow-up over which period vaccine efficacy against new Plasmodium falciparum infections was estimated at 65.9% (95% CI 42.6-79.8, p<0.0001). We now report safety, immunogenicity and estimated efficacy against clinical malaria up to 14 months after study start. Vaccine efficacy was assessed using Cox regression models. The frequency of serious adverse events was 32.7% in the RTS,S/AS02(D) and 31.8% in the control group. The geometric mean titers of anti-circumsporozoite antibodies declined from 199.9 to 7.3 EU/mL from one to 12 months post dose three of RTS,S/AS02(D), remaining 15-fold higher than in the control group. Vaccine efficacy against clinical malaria was 33% (95% CI: -4.3-56.9, p = 0.076) over 14 months of follow-up. The hazard rate of disease per 2-fold increase in anti-CS titters was reduced by 84% (95% CI 35.1-88.2, p = 0.003).The RTS,S/AS02(D) malaria vaccine administered to young infants has a good safety profile and remains efficacious over 14 months. A strong association between anti-CS antibodies and risk of clinical malaria has been described for the first time. The results also suggest a decrease of both anti-CS antibodies and vaccine efficacy over time.ClinicalTrials.gov NCT00197028

Ecology and technological capability of lactic acid bacteria isolated during Grillo grape vinification in the Marsala production area.

Grapes of “Grillo” variety, used to produce Marsala wine, were harvested from five vineyards different for climatic and agronomic parameters, in order to obtain a first mapping of lactic acid bacteria (LAB) inhabiting the production area. Marsala base wine production was followed at large-scale and two experimental vinifications, different for lysozyme and SO2 concentration and combination, were carried out at pilot-plant scale. LAB communities and conventional chemical parameters were periodically analysed. LAB were found on grapes at an average concentration of about 102 CFU g-1 which decreased during the transformation process. A total of 146 colonies were collected, but only 35 were recognized as presumptive LAB. On the basis of phenotypic differences and isolation source, 16 isolates were then subjected to genotypic identification and gathered into the following species: Lactococcus lactis subsp. lactis, Lactococcus lactis subsp. cremoris, Enterococcus faecium, Leuconostoc fallax and Sporalactobacillus nakayamae subsp. nakayamae. Lactococcus lactis subsp. lactis strains was the species most frequently isolated during winemaking showing the highest resistance to SO2 and lysozyme

Insights into Long-Lasting Protection Induced by RTS,S/AS02A Malaria Vaccine: Further Results from a Phase IIb Trial in Mozambican Children

Background: The pre-erythrocytic malaria vaccine RTS,S/AS02A has shown to confer protection against clinical malaria for at least 21 months in a trial in Mozambican children. Efficacy varied between different endpoints, such as parasitaemia or clinical malaria; however the underlying mechanisms that determine efficacy and its duration remain unknown. We performed a new, exploratory analysis to explore differences in the duration of protection among participants to better understand the protection afforded by RTS,S. Methodology/Principal Findings: The study was a Phase IIb double-blind, randomized controlled trial in 2022 children aged 1 to 4 years. The trial was designed with two cohorts to estimate vaccine efficacy against two different endpoints: clinical malaria (cohort 1) and infection (cohort 2). Participants were randomly allocated to receive three doses of RTS,S/AS02A or control vaccines. We did a retrospective, unplanned sub-analysis of cohort 2 data using information collected for safety through the health facility-based passive case detection system. Vaccine efficacy against clinical malaria was estimated over the first six-month surveillance period (double-blind phase) and over the following 12 months (single-blind phase), and analysis was per-protocol. Adjusted vaccine efficacy against first clinical malaria episodes in cohort 2 was of 35.4% (95% CI 4.5-56.3; p = 0.029) over the double-blind phase and of 9.0% (230.6-36.6; p = 0.609) during the single-blind phase. Conclusions/Significance: Contrary to observations in cohort 1, where efficacy against clinical malaria did not wane over time, in cohort 2 the efficacy decreases with time. We hypothesize that this reduced duration of protection is a result of the early diagnosis and treatment of infections in cohort 2 participants, preventing sufficient exposure to asexual-stage antigens. On the other hand, the long-term protection against clinical disease observed in cohort 1 may be a consequence of a prolonged exposure to low-dose blood-stage asexual parasitaemia

Shape model and spin-state analysis of PHA contact binary (85990) 1999 JV6 from combined radar and optical observations

Context. The potentially hazardous asteroid (85990)1999 JV6 has been a target of previously published thermal-infrared observations and optical photometry. It has been identified as a promising candidate for possible Yarkovsky-O’Keefe-Radzievskii-Paddack (YORP) effect detection. Aims. The YORP effect is a small thermal-radiation torque considered to be a key factor in spin-state evolution of small Solar System bodies. In order to detect YORP on 1999 JV6 we developed a detailed shape model and analysed the spin-state using both optical and radar observations. Methods. For 1999 JV6, we collected optical photometry between 2007 and 2016. Additionally, we obtained radar echo-power spectra and imaging observations with Arecibo and Goldstone planetary radar facilities in 2015, 2016, and 2017. We combined our data with published optical photometry to develop a robust physical model. Results. We determine that the rotation pole resides at negative latitudes in an area with a 5◦ radius close to the south ecliptic pole. The refined sidereal rotation period is 6.536787±0.000007 h. The radar images are best reproduced with a bilobed shape model. Both lobes of 1999 JV6 can be represented as oblate ellipsoids with a smaller, more spherical component resting at the end of a larger, more elongated component. While contact binaries appear to be abundant in the near-Earth population, there are only a few published shape models for asteroids in this particular configuration. By combining the radar-derived shape model with optical light curves we determine a constant-period solution that fits all available data well. Using light-curve data alone we determine an upper limit for YORP of 8.5×10−8 rad day−2. Conclusions. The bifurcated shape of 1999 JV6 might be a result of two ellipsoidal components gently merging with each other, or a deformation of a rubble pile with a weak-tensile-strength core due to spin-up. The physical model of 1999 JV6 presented here will enable future studies of contact binary asteroid formation and evolution

Narrow-band Imaging for Detection of Neoplasia at Colonoscopy: a Meta-analysis of Data From Individual Patients in Randomized Controlled Trials

Background & Aims Adenoma detection rate (ADR) is an important quality assurance measure for colonoscopy. Some studies suggest that narrow band imaging (NBI) may be more effective at detection of adenomas than white-light endoscopy (WLE) when bowel preparation is optimal. We conducted a meta-analysis of data from individual patients in randomized controlled trials that compared the efficacy of NBI to WLE in detection of adenomas. Methods We searched MEDLINE, EMBASE, and Cochrane library databases, through April 2017, for randomized controlled trials that assessed detection of colon polyps by high-definition WLE vs NBI and from which data on individual patients was available. The primary outcome measure was ADR adjusted for bowel preparation quality. Multilevel regression models were used with patients nested within trials, and trial included as a random effect. Results We collected data from 11 trials, comprising 4491 patients and 6636 polyps detected. Adenomas were detected in 952/2251 (42.3%) participants examined by WLE vs 1011/2239 (45.2%) participants examined by NBI (unadjusted odds ratio [OR] for detection of adenoma by WLE vs NBI, 1.14; 95% CI, 1.01–1.29; P=.04). NBI outperformed WLE only when bowel preparation was best: adequate preparation OR, 1.07 (95% CI, 0.92–1.24; P=.38) vs best preparation OR, 1.30 (95% CI, 1.04–1.62; P=.02). Second-generation bright NBI had a better ADR than WLE (second-generation NBI OR, 1.28; 95% CI, 1.05–1.56; P=.02), whereas first-generation NBI did not. NBI detected more non-adenomatous polyps than WLE (OR, 1.24; 95% CI, 1.06–1.44; P=.008) and flat polyps than WLE (OR, 1.24; 95% CI, 1.02–1.51; P=.03). Conclusions In a meta-analysis of data from individual patients in randomized controlled trials, we found NBI to have a higher ADR than WLE, and that this effect is greater when bowel preparation is optimal

Absence of association of asporin polymorphisms and osteoarthritis susceptibility in US Caucasians

An association between osteoarthritis (OA) and functional polymorphisms in the aspartic acid (D) repeat of the asporin (ASPN) gene was reported in Japanese and Han Chinese populations. The aim of this study was to assess the association of variants in the ASPN gene with the presence of radiographic hand and/or knee OA in a US Caucasian population

Impact of RTS,S/AS02A and RTS,S/AS01B on Genotypes of P. falciparum in Adults Participating in a Malaria Vaccine Clinical Trial

Objective:RTS,S, a candidate vaccine for malaria, is a recombinant protein expressed in yeast containing part of the circumsporozoite protein (CSP) sequence of 3D7 strain of Plasmodium falciparum linked to the hepatitis B surface antigen in a hybrid protein. The RTS,S antigen is formulated with GSK Biologicals\u27 proprietary Adjuvant Systems AS02A or AS01B. A recent trial of the RTS,S/AS02A and RTS,S/AS01B vaccines evaluated safety, immunogenicity and impact on the development of parasitemia of the two formulations. Parasite isolates from this study were used to determine the molecular impact of RTS,S/AS02A and RTS,S/AS01B on the multiplicity of infection (MOI) and the csp allelic characteristics of subsequent parasitemias.Design:The distribution of csp sequences and the MOI of the infecting strains were examined at baseline and in break-through infections from vaccinated individuals and from those receiving a non-malarial vaccine.Setting:The study was conducted in Kombewa District, western Kenya.Participants:Semi-immune adults from the three study arms provided isolates at baseline and during break-through infections.Outcome:Parasite isolates used for determining MOI and divergence of csp T cell&ndash;epitopes were 191 at baseline and 87 from break-through infections.Results:Grouping recipients of RTS,S/AS01A and RTS,S/AS02B together, vaccine recipients identified as parasite-positive by microscopy contained significantly fewer parasite genotypes than recipients of the rabies vaccine comparator (median in pooled RTS,S groups: 3 versus 4 in controls, P = 0.0313). When analyzed separately, parasitaemic individuals in the RTS,S/AS01B group, but not the RTS,S/AS02A group, were found to have significantly fewer genotypes than the comparator group. Two individual amino acids found in the vaccine construct (Q339 in Th2R and D371 in Th3R) were observed to differ in incidence between vaccine and comparator groups but in different directions; parasites harboring Q339 were less common among pooled RTS,S/AS vaccine recipients than among recipients of rabies vaccine, whereas parasites with D371 were more common among the RTS,S/AS groups.Conclusions:It is concluded that both RTS,S/AS vaccines reduce multiplicity of infection. Our results do not support the hypothesis that RTS,S/AS vaccines elicit preferential effects against pfcsp alleles with sequence similarity to the 3D7 pfcsp sequence employed in the vaccine construct