The applications of Western/immunoblotting (WB) techniques have reached multiple layers of the scientific community and are now considered routine procedures in the field of physiology. This is none ...more so than in relation to skeletal muscle physiology (i.e., resolving the mechanisms underpinning adaptations to exercise). Indeed, the inclusion of WB data is now considered an essential aspect of many such physiological publications to provide mechanistic insight into regulatory processes. Despite this popularity, and due to the ubiquitous and relatively inexpensive availability of WB equipment, the quality of WB in publications and subsequent analysis and interpretation of the data can be variable, perhaps resulting in spurious conclusions. This may be due to poor laboratory technique and/or lack of comprehension of the critical steps involved in WB and what quality control procedures should be in place to ensure robust data generation. The present review aims to provide a detailed description and critique of WB procedures and technicalities, from sample collection through preparation, blotting and detection, to analysis of the data collected. We aim to provide the reader with improved expertise to critically conduct, evaluate, and troubleshoot the WB process, to produce reproducible and reliable blots.
In this paper, we describe the first data release of the Visible and Infrared Survey Telescope for Astronomy (VISTA) Deep Extragalactic Observations (VIDEO) survey. VIDEO is a ∼12 deg2 survey in the ...near-infrared Z, Y, J, H and K
s bands, specifically designed to enable the evolution of galaxies and large structures to be traced as a function of both epoch and environment from the present day out to z = 4, and active galactic nuclei (AGNs) and the most massive galaxies up to and into the epoch of reionization. With its depth and area, VIDEO will be able to fully explore the period in the Universe where AGN and starburst activity were at their peak and the first galaxy clusters were beginning to virialize. VIDEO therefore offers a unique data set with which to investigate the interplay between AGN, starbursts and environment, and the role of feedback at a time when it was potentially most crucial.
We provide data over the VIDEO-XMM3 tile, which also covers the Canada-France-Hawaii Telescope Legacy Survey Deep-1 field (CFHTLS-D1). The released VIDEO data reach a 5σ AB-magnitude depth of Z = 25.7, Y = 24.5, J = 24.4, H = 24.1 and K
s = 23.8 in 2 arcsec diameter apertures (the full depth of Y = 24.6 will be reached within the full integration time in future releases). The data are compared to previous surveys over this field and we find good astrometric agreement with the Two Micron All Sky Survey, and source counts in agreement with the recently released UltraVISTA survey data. The addition of the VIDEO data to the CFHTLS-D1 optical data increases the accuracy of photometric redshifts and significantly reduces the fraction of catastrophic outliers over the redshift range 0 < z < 1 from 5.8 to 3.1 per cent in the absence of an i-band luminosity prior. However, we expect that the main improvement in photometric redshifts will come in the redshift range 1 < z < 4 due to the sensitivity to the Balmer and 4000 Å breaks provided by the near-infrared VISTA filters. All images and catalogues presented in this paper are publicly available through ESO's phase 3 archive and the VISTA Science Archive.
Summary
Background
The ‘treat to target’ paradigm improves outcomes and reduces costs in chronic disease management but is not yet established in psoriasis.
Objectives
To identify treatment targets ...in psoriasis using two common measures of disease activity: Psoriasis Area and Severity Index (PASI) and Physician's Global Assessment (PGA).
Methods
Data from a multicentre longitudinal U.K. cohort of patients with psoriasis receiving systemic or biologic therapies (British Association of Dermatologists Biologics and Immunomodulators Register, BADBIR) were used to identify absolute PASI thresholds for 90% (PASI 90) and 75% (PASI 75) improvements in baseline disease activity, using receiver operating characteristic curves. The relationship between PGA (clear, almost clear, mild, moderate, moderate–severe, severe) and PASI (range 0–72) was described, and the concordance between absolute and relative definitions of response was determined. The same approach was used to establish treatment response and eligibility definitions based on PGA.
Results
Data from 13 422 patients were available (58% male, 91% white ethnicity, mean age 44·9 years), including over 23 000 longitudinal PASI and PGA scores. An absolute PASI ≤ 2 was concordant with PASI 90 and an absolute PASI ≤ 4 was concordant with PASI 75 in 90% and 88% of cases, respectively. These findings were robust to subgroups of timing of assessment, baseline disease severity and treatment modality. PASI and PGA were strongly correlated (Spearman's rank correlation coefficient 0·92). The median PASI increased from 0 (interquartile range 0–0, range 0–23) to 19 (interquartile range 15–25, range 0–64) for PGA clear to severe, respectively. PGA clear/almost clear was concordant with PASI ≤ 2 in 90% of cases, and PGA moderate–severe severe was concordant with the National Institute for Health and Care Excellence PASI eligibility criteria for biologics in 81% of cases.
Conclusions
An absolute PASI ≤ 2 and PGA clear/almost clear represent relevant disease end points to inform treat‐to‐target management strategies in psoriasis.
What's already known about this topic?
The most commonly used relative disease activity measure in psoriasis is ≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90); however, it has several limitations including dependency on a baseline severity assessment.
Defining an absolute target disease activity end point in psoriasis has the potential to improve patient outcomes and reduce costs, as demonstrated by treat‐to‐target approaches in other chronic diseases such as hypertension and diabetes.
The Physician's Global Assessment (PGA) is a popular alternative measure of psoriasis severity in daily practice; however, its utility has not been formally assessed with respect to PASI.
What does this study add?
An absolute PASI ≤ 2 corresponds with PASI 90 response and is a relevant disease end point for treat‐to‐target approaches in psoriasis.
There is a strong correlation between PASI and PGA.
PGA moderate–severe/severe may serve as an alternative eligibility criterion for biologics to PASI‐based definitions, and PGA clear/almost clear is an appropriate alternative absolute treatment end point.
What are the clinical implications of this work?
Absolute PASI ≤ 2 and PGA clear/almost clear represent relevant disease end points to inform treat‐to‐target management strategies in psoriasis.
Linked Editorial: Takeshita. Br J Dermatol 2020; 182:1075–1076.
The flare of radiation from the tidal disruption and accretion of a star can be used as a marker for supermassive black holes that otherwise lie dormant and undetected in the centres of distant ...galaxies. Previous candidate flares have had declining light curves in good agreement with expectations, but with poor constraints on the time of disruption and the type of star disrupted, because the rising emission was not observed. Recently, two 'relativistic' candidate tidal disruption events were discovered, each of whose extreme X-ray luminosity and synchrotron radio emission were interpreted as the onset of emission from a relativistic jet. Here we report a luminous ultraviolet-optical flare from the nuclear region of an inactive galaxy at a redshift of 0.1696. The observed continuum is cooler than expected for a simple accreting debris disk, but the well-sampled rise and decay of the light curve follow the predicted mass accretion rate and can be modelled to determine the time of disruption to an accuracy of two days. The black hole has a mass of about two million solar masses, modulo a factor dependent on the mass and radius of the star disrupted. On the basis of the spectroscopic signature of ionized helium from the unbound debris, we determine that the disrupted star was a helium-rich stellar core.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Nearly all general circulation models significantly fail to reproduce the observed behaviour of the southern wintertime polar vortex. It has been suggested that these biases result from an ...underestimation of gravity wave drag on the atmosphere at latitudes near 60° S, especially around the "hot spot" of intense gravity wave fluxes above the mountainous Southern Andes and Antarctic peninsula. Here, we use Global Positioning System radio occultation (GPS-RO) data from the COSMIC satellite constellation to determine the properties of gravity waves in the hot spot and beyond. We show considerable southward propagation to latitudes near 60° S of waves apparently generated over the southern Andes. We propose that this propagation may account for much of the wave drag missing from the models. Furthermore, there is a long leeward region of increased gravity wave energy that sweeps eastwards from the mountains over the Southern Ocean. Despite its striking nature, the source of this region has historically proved difficult to determine. Our observations suggest that this region includes both waves generated locally and orographic waves advected downwind from the hot spot. We describe and use a new wavelet-based analysis technique for the quantitative identification of individual waves from COSMIC temperature profiles. This analysis reveals different geographical regimes of wave amplitude and short-timescale variability in the wave field over the Southern Ocean. Finally, we use the increased numbers of closely spaced pairs of profiles from the deployment phase of the COSMIC constellation in 2006 to make estimates of gravity wave horizontal wavelengths. We show that, given sufficient observations, GPS-RO can produce physically reasonable estimates of stratospheric gravity wave momentum flux in the hot spot that are consistent with measurements made by other techniques. We discuss our results in the context of previous satellite and modelling studies and explain how they advance our understanding of the nature and origins of waves in the southern stratosphere.
The Observations and Modeling of the Green Ocean Amazon (GoAmazon2014/5) Experiment was carried out in the environs of Manaus, Brazil, in the central region of the Amazon basin for 2 years from ...1 January 2014 through 31 December 2015. The experiment focused on the complex interactions among vegetation, atmospheric chemistry, and aerosol production on the one hand and their connections to aerosols, clouds, and precipitation on the other. The objective was to understand and quantify these linked processes, first under natural conditions to obtain a baseline and second when altered by the effects of human activities. To this end, the pollution plume from the Manaus metropolis, superimposed on the background conditions of the central Amazon basin, served as a natural laboratory. The present paper, as the introduction to the special issue of GoAmazon2014/5, presents the context and motivation of the GoAmazon2014/5 Experiment. The nine research sites, including the characteristics and instrumentation of each site, are presented. The sites range from time point zero (T0) upwind of the pollution, to T1 in the midst of the pollution, to T2 just downwind of the pollution, to T3 furthest downwind of the pollution (70 km). In addition to the ground sites, a low-altitude G-159 Gulfstream I (G-1) observed the atmospheric boundary layer and low clouds, and a high-altitude Gulfstream G550 (HALO) operated in the free troposphere. During the 2-year experiment, two Intensive Operating Periods (IOP1 and IOP2) also took place that included additional specialized research instrumentation at the ground sites as well as flights of the two aircraft. GoAmazon2014/5 IOP1 was carried out from 1 February to 31 March 2014 in the wet season. GoAmazon2014/5 IOP2 was conducted from 15 August to 15 October 2014 in the dry season. The G-1 aircraft flew during both IOP1 and IOP2, and the HALO aircraft flew during IOP2. In the context of the Amazon basin, the two IOPs also correspond to the clean and biomass burning seasons, respectively. The Manaus plume is present year-round, and it is transported by prevailing northeasterly and easterly winds in the wet and dry seasons, respectively. This introduction also organizes information relevant to many papers in the special issue. Information is provided on the vehicle fleet, power plants, and industrial activities of Manaus. The mesoscale and synoptic meteorologies relevant to the two IOPs are presented. Regional and long-range transport of emissions during the two IOPs is discussed based on satellite observations across South America and Africa. Fire locations throughout the airshed are detailed. In conjunction with the context and motivation of GoAmazon2014/5 as presented in this introduction, research articles including thematic overview articles are anticipated in this special issue to describe the detailed results and findings of the GoAmazon2014/5 Experiment.
BRCA1 and BRCA2 are important for DNA double-strand break repair by homologous recombination, and mutations in these genes predispose to breast and other cancers. Poly(ADP-ribose) polymerase (PARP) ...is an enzyme involved in base excision repair, a key pathway in the repair of DNA single-strand breaks. We show here that BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis. This seems to be because the inhibition of PARP leads to the persistence of DNA lesions normally repaired by homologous recombination. These results illustrate how different pathways cooperate to repair damage, and suggest that the targeted inhibition of particular DNA repair pathways may allow the design of specific and less toxic therapies for cancer.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aerosol Jet Printing (AJP) is an emerging contactless direct write approach aimed at the production of fine features on a wide range of substrates. Originally developed for the manufacture of ...electronic circuitry, the technology has been explored for a range of applications, including, active and passive electronic components, actuators, sensors, as well as a variety of selective chemical and biological responses. Freeform deposition, coupled with a relatively large stand-off distance, is enabling researchers to produce devices with increased geometric complexity compared to conventional manufacturing or more commonly used direct write approaches. Wide material compatibility, high resolution and independence of orientation have provided novelty in a number of applications when AJP is conducted as a digitally driven approach for integrated manufacture. This overview of the technology will summarise the underlying principles of AJP, review applications of the technology and discuss the hurdles to more widespread industry adoption. Finally, this paper will hypothesise where gains may be realised through this assistive manufacturing process.
PDF
