The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) promoter 1 (LP1) is an inducible and cell type-specific promoter involved in regulating the production of an 8.3-kb primary ...LAT transcript during acute and latent infection of peripheral sensory neurons and during subsequent virus reactivation. A number of cis-acting regulatory elements have been identified in LP1, including two cyclic-AMP (cAMP) response element (CRE)-like sequences, designated CRE-1 and CRE-2. CRE-1 has previously been shown to confer cAMP responsiveness to LP1 and to regulate reactivation of HSV-1 from latency in vivo. A role for CRE-2 in modulating inducible activity is not yet as clear; however, it has been shown to support basal expression in neuronal cells in vitro. Electrophoretic mobility shift (EMS) analyses demonstrate that the LP1 CRE-like elements interact with distinct subsets of neuronal ATF/CREB and Jun/Fos proteins including CREB-1, CREB-2, ATF-1, and JunD. The factor-binding properties of each LP1 CRE element distinguish them from each other and from a highly related canonical CRE binding site and the TPA response element (TRE). LP1 CRE-1 shares binding characteristics of both a canonical CRE and a TRE. LP1 CRE-2 is more unusual in that it shares more features of a canonical CRE site than a TRE with two notable exceptions: it does not bind CREB-1 very well and it binds CREB-2 better than the canonical CRE. Interestingly, a substantial proportion of the C1300 neuroblastoma factors that bind to CRE-1 and CRE-2 have been shown to be immunologically related to JunD, suggesting that the AP-1 family of transcription factors may be important in regulating CRE-dependent LP1 transcriptional activity. In addition, we have demonstrated the two HSV-1 LP1 CRE sites to be unique with respect to their ability to bind neuronal AP1-related factors that are regulated by cAMP. These studies suggest that both factor binding and activation of bound factors may be involved in cAMP regulation of HSV-1 LP1 through the CRE elements, and indicate the necessity of investigating the expression and posttranslational modification of a variety of ATF/CREB and AP-1 factors during latency and reactivation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Delays in diagnostic testing after a positive result from a screening test can undermine the benefits of colorectal cancer (CRC) screening, but there are few empirical data on the effects of such ...delays. We used microsimulation modeling to estimate the consequences of time to colonoscopy after a positive result from a fecal immunochemical test (FIT).
We used an established microsimulation model to simulate an average-risk United States population cohort that underwent annual FIT screening (from ages 50 to 75 years), with follow-up colonoscopy examinations for individuals with positive results (cutoff, 20 μg/g) at different time points in the following 12 months. Main evaluated outcomes were CRC incidence and mortality; additional outcomes were total life-years lost and net costs of screening.
For individuals who underwent diagnostic colonoscopy within 2 weeks of a positive result from an FIT, the estimated lifetime risk of CRC incidence was 35.5/1000 persons, and mortality was 7.8/1000 persons. Every month added until colonoscopy was associated with a 0.1/1000 person increase in cancer incidence risk (an increase of 0.3%/month, compared with individuals who received colonoscopies within 2 weeks) and mortality risk (increase of 1.4%/month). Among individuals who received colonoscopy examinations 12 months after a positive result from an FIT, the incidence of CRC was 27.0/1000 persons (increase of 4%, compared with 2 weeks), and mortality was 9.1/1000 persons (increase of 16%). Total years of life gained for the entire screening cohort decreased from an estimated 93.7/1000 persons with an almost immediate follow-up colonoscopy (cost savings of $208 per patient, compared with no colonoscopy) to 84.8/1000 persons with follow-up colonoscopies at 12 months (decrease of 9%; cost savings of $100/patient, compared with no colonoscopy).
By using a microsimulation model of an average-risk United States screening cohort, we estimated that delays of up to 12 months after a positive result from an FIT can produce proportional losses of up to nearly 10% in overall screening benefits. These findings indicate the importance of timely follow-up colonoscopy examinations of patients with positive results from FITs.
•Missing link in crustacean ecdysone hydroxylation identified.•Metamorphic expression implicates un-annotated CYP450s in ecdysteroidogenesis.•CYPome of a spiny lobster enables annotation of known ...CYP450s based on insects.
Cytochrome P450s (CYP450s) are a rapidly evolving family of enzymes, making it difficult to identify bona fide orthologs with notable lineage-specific exceptions. In ecdysozoans, a small number of the most conserved orthologs include enzymes which metabolize ecdysteroids. Ecdysone pathway components were recently shown in a decapod crustacean but with a notable absence of shade, which is important for converting ecdysone to its active form, 20-hydroxyecdysone (20HE), suggesting that another CYP450 performs a similar function in crustaceans. A CYPome temporal expression analysis throughout metamorphosis performed in this research highlights several un-annotated CYP450s displaying differential expression and provides information into expression patterns of annotated CYP450s. Using the expression patterns in the Eastern spiny lobster Sagmariasus verreauxi, followed by 3D modelling and finally activity assays in vitro, we were able to conclude that a group of CYP450s, conserved across decapod crustaceans, function as the insect shade. To emphasize the fact that these genes share the function with shade but are phylogenetically distinct, we name this enzyme system Shed.
ABSTRACT
We report the discovery of two mini-Neptunes in near 2:1 resonance orbits (P = 7.610303 d for HIP 113103 b and P = 14.245651 d for HIP 113103 c) around the adolescent K-star HIP 113103 (TIC ...121490076). The planet system was first identified from the TESS mission, and was confirmed via additional photometric and spectroscopic observations, including a ∼17.5 h observation for the transits of both planets using ESA CHEOPS. We place ≤4.5 min and ≤2.5 min limits on the absence of transit timing variations over the 3 yr photometric baseline, allowing further constraints on the orbital eccentricities of the system beyond that available from the photometric transit duration alone. With a planetary radius of Rp = $1.829_{-0.067}^{+0.096}$ R⊕, HIP 113103 b resides within the radius gap, and this might provide invaluable information on the formation disparities between super-Earths and mini-Neptunes. Given the larger radius Rp = $2.40_{-0.08}^{+0.10}$ R⊕ for HIP 113103 c, and close proximity of both planets to HIP 113103, it is likely that HIP 113103 b might have lost (or is still losing) its primordial atmosphere. We therefore present simulated atmospheric transmission spectra of both planets using JWST, HST, and Twinkle. It demonstrates a potential metallicity difference (due to differences in their evolution) would be a challenge to detect if the atmospheres are in chemical equilibrium. As one of the brightest multi sub-Neptune planet systems suitable for atmosphere follow up, HIP 113103 b and HIP 113103 c could provide insight on planetary evolution for the sub-Neptune K-star population.
A semi-distributed model, INCA, has been developed to determine the fate and distribution of nutrients in terrestrial and aquatic systems. The model simulates nitrogen and phosphorus processes in ...soils, groundwaters and river systems and can be applied in a semi-distributed manner at a range of scales. In this study, the model has been applied at field to sub-catchment to whole catchment scale to evaluate the behaviour of biosolid-derived losses of P in agricultural systems. It is shown that process-based models such as INCA, applied at a wide range of scales, reproduce field and catchment behaviour satisfactorily. The INCA model can also be used to generate generic information for risk assessment. By adjusting three key variables: biosolid application rates, the hydrological connectivity of the catchment and the initial P-status of the soils within the model, a matrix of P loss rates can be generated to evaluate the behaviour of the model and, hence, of the catchment system. The results, which indicate the sensitivity of the catchment to flow paths, to application rates and to initial soil conditions, have been incorporated into a Nutrient Export Risk Matrix (NERM).
Background
Screening outreach programs using population health management principles offer services uniformly to all eligible persons, but racial/ethnic colorectal cancer (CRC) screening patterns in ...such programs are not well known.
Objective
To examine the association between race/ethnicity and the receipt of CRC screening and timely follow-up of positive results before and after implementation of a screening program.
Design
Retrospective cohort study of screen-eligible individuals at the Kaiser Permanente Northern California community-based integrated healthcare delivery system (2004–2013).
Subjects
A total of 868,934 screen-eligible individuals 51–74 years of age at cohort entry, which included 662,872 persons in the period before program implementation (2004–2006), 654,633 during the first 3 years after implementation (2007–2009), and 665,268 in the period from 4 to 7 years (2010–2013) after program implementation.
Intervention
A comprehensive system-wide long-term effort to increase CRC that included leadership alignment, goal-setting, and quality assurance through a PHM approach, using mailed fecal immunochemical testing (FIT) along with offering screening at office visits.
Main Measures
Differences over time and by race/ethnicity in up-to-date CRC screening (overall and by test type) and timely follow-up of a positive screen. Race/ethnicity categories included non-Hispanic white, non-Hispanic black, Hispanic/Latino, Asian/Pacific Islander, Native American, and multiple races.
Key Results
From 2004 to 2013, age/sex-adjusted CRC screening rates increased in all groups, including 35.2 to 81.1 % among whites and 35.6 to 78.0 % among blacks. Screening rates among Hispanics (33.1 to 78.3 %) and Native Americans (29.4 to 74.5 %) remained lower than those for whites both before and after program implementation. Blacks, who had slightly higher rates before program implementation (adjusted rate ratio RR = 1.04, 99 % CI: 1.02–1.05), had lower rates after program implementation (RR for period from 4 to 7 years = 0.97, 99 % CI: 0.96–0.97). There were also substantial improvements in timely follow-up of positive screening results.
Conclusions
In this screening program using core PHM principles, CRC screening increased markedly in all racial/ethnic groups, but disparities persisted for some groups and developed in others, which correlated with levels of adoption of mailed FIT.
We present the results of the first complete unbaised survey of the Galactic plane for 6035-MHz excited-state hydroxyl (ex-OH) masers undertaken as part of the methanol multibeam (MMB) survey. These ...observations cover the Galactic longitude ranges 186° < l < 60° including the Galactic Centre. We report the detection of 127 ex-OH masers within the survey region, 47 being new sources. The positions of new detections were determined from interferometric observations with the Australia Telescope Compact Array. We discuss the association of 6035-MHz masers in our survey with the 6668-MHz masers from the MMB Survey, finding 37 likely CH3OH–ex-OH maser pairs with physical separations of ≤0.03 pc and 55 pairings separated by ≤0.1 pc. Using these we calculate for the first time an ex-OH maser lifetime of between 3.3 × 103 and 8.3 × 103 yr. We also discuss the variability of the 6035-MHz masers and detection rates of counterpart 6030-MHz ex-OH masers (28 per cent of our sample having detection at both frequencies).
We describe the design and current performance of a 14.5 T hybrid linear quadrupole ion trap Fourier transform ion cyclotron resonance mass spectrometer. Ion masses are routinely determined at 4-fold ...better mass accuracy and 2-fold higher resolving power than similar 7 T systems at the same scan rate. The combination of high magnetic field and strict control of the number of trapped ions results in external calibration broadband mass accuracy typically less than 300 ppb rms, and a resolving power of 200 000 (m/Δm 50% at m/z 400) is achieved at greater than 1 mass spectrum per second. Novel ion storage optics and methodology increase the maximum number of ions that can be delivered to the FTICR cell, thereby improving dynamic range for tandem mass spectrometry and complex mixture applications.
Abstract
We explore the circumgalactic medium (CGM) of two simulated star-forming galaxies with luminosities L ≈ 0.1 and 1 L
⋆ generated using the smooth particle hydrodynamic code gasoline. These ...simulations are part of the Making Galaxies In a Cosmological Context (magicc) program in which the stellar feedback is tuned to match the stellar mass-halo mass relationship. For comparison, each galaxy was also simulated using a 'lower feedback' (LF) model which has strength comparable to other implementations in the literature. The 'magicc feedback' (MF) model has a higher incidence of massive stars and an approximately two times higher energy input per supernova. Apart from the low-mass halo using LF, each galaxy exhibits a metal-enriched CGM that extends to approximately the virial radius. A significant fraction of this gas has been heated in supernova explosions in the disc and subsequently ejected into the CGM where it is predicted to give rise to substantial O vi absorption. The simulations do not yet address the question of what happens to the O vi when the galaxies stop forming stars. Our models also predict a reservoir of cool H i clouds that show strong Lyα absorption to several hundred kpc. Comparing these models to recent surveys with the Hubble Space Telescope, we find that only the MF models have sufficient O vi and H i gas in the CGM to reproduce the observed distributions. In separate analyses, these same MF models also show better agreement with other galaxy observables (e.g. rotation curves, surface brightness profiles and H i gas distribution). We infer that the CGM is the dominant reservoir of baryons for galaxy haloes.
The application of direct-current plasma arc furnace technology to the problem of coal gasification is investigated using computational multiphysics models of the plasma arc inside such units. An ...integrated modelling workflow for the study of DC plasma arc discharges in synthesis gas atmospheres is presented. The thermodynamic and transport properties of the plasma are estimated using statistical mechanics calculations and are shown to have highly non-linear dependencies on the gas composition and temperature. A computational magnetohydrodynamic solver for electromagnetically coupled flows is developed and implemented in the OpenFOAM® framework, and the behaviour of three-dimensional transient simulations of arc formation and dynamics is studied in response to different plasma gas compositions and furnace operating conditions. To demonstrate the utility of the methods presented, practical engineering results are obtained from an ensemble of simulation results for a pilot-scale furnace design. These include the stability of the arc under different operating conditions and the dependence of voltage–current relationships on the arc length, which are relevant in understanding the industrial operability of plasma arc furnaces used for waste coal gasification.
PDF
