We examine the early phase intrinsic (B − V)0 color evolution of a dozen SNe Ia discovered within three days of the inferred time of first light (tfirst) and have (B − V)0 color information beginning ...within five days of tfirst. The sample indicates there are two distinct early populations. The first is a population exhibiting blue colors that slowly evolve, and the second population exhibits red colors and evolves more rapidly. We find that the early blue events are all 1991T/1999aa-like with more luminous, slower declining light curves than those exhibiting early red colors. Placing the first sample on the Branch diagram (i.e., ratio of Si ii λλ5972, 6355 pseudo-Equivalent widths) indicates that all blue objects are of the Branch shallow silicon (SS) spectral type, while all early red events except for the 2000cx-like SN 2012fr are of the Branch Core Normal (CN) or CooL (CL) type. A number of potential processes contributing to the early emission are explored, and we find that, in general, the viewing-angle dependance inherent in the companion collision model is inconsistent with all of the SS objects with early-time observations being blue and exhibiting an excess. We caution that great care must be taken when interpreting early phase light curves as there may be a variety of physical processes that are possibly at play and significant theoretical work remains to be done.
Summary
Background
There is no defined set of criteria for diagnosing erosive lichen planus affecting the vulva (ELPV) and there is geographical variation in management.
Objectives
To reach consensus ...on clinicopathological diagnostic criteria for ELPV.
Methods
This was a three‐stage international electronic‐Delphi exercise with a subsequent formal feedback process. In the first two rounds participants were asked to rate the importance of a list of clinicopathological criteria. Responses from round 1 were summarized and presented in round 2, along with additional criteria suggested by participants. In round 3, participants were asked to rate the items that had reached consensus as ‘essential’ or ‘supportive’ features in diagnosing ELPV. Consensus was defined as being reached if 75% of participants agreed on the importance of an item.
Results
A total of 73 experts representing dermatology, gynaecology, histopathology and genitourinary medicine participated; 69 (95%) completed all three rounds. Consensus was achieved for the following ‘supportive’ diagnostic criteria: (i) well‐demarcated erosions/erythematous areas at the vaginal introitus; (ii) presence of a hyperkeratotic border to lesions and/or Wickham striae in surrounding skin; (iii) symptoms of pain/burning; (iv) scarring/loss of normal architecture; (v) presence of vaginal inflammation; (vi) involvement of other mucosal surfaces; (vii) presence of a well‐defined inflammatory band involving the dermoepidermo junction; (viii) presence of an inflammatory band consisting predominantly of lymphocytes; and (ix) signs of basal layer degeneration. It was suggested that at least three supportive features should be present to make a diagnosis of ELPV, although this number is subject to further discussion.
Conclusions
This study has identified a diagnostic dataset for ELPV that can be adopted into clinical practice and clinical trials.
What's already known about this topic?
Erosive lichen planus affecting the vulva (ELPV) is an uncommon inflammatory dermatosis that is often resistant to first‐line therapy.
There are no published criteria for the diagnosis of ELPV.
What does this study add?
Using the electronic‐Delphi technique we have collated a set of nine diagnostic criteria internationally agreed by physicians with expertise in the diagnosis and management of vulval disease including ELPV.
It is thought that at least three out of the nine supportive criteria should be present in order to diagnose ELPV, but this number requires further validation.
This diagnostic dataset will guide the clinical diagnosis of ELPV and will standardize the inclusion of patients into clinical trials.
The British Society of Gastroenterology (BSG) and the Association of Coloproctology for Great Britain and Ireland (ACPGBI) commissioned this update of the 2002 guidance. The aim, as before, is to ...provide guidance on the appropriateness, method and frequency of screening for people at moderate and high risk from colorectal cancer. This guidance provides some new recommendations for those with inflammatory bowel disease and for those at moderate risk resulting from a family history of colorectal cancer. In other areas guidance is relatively unchanged, but the recent literature was reviewed and is included where appropriate.
Loading of the eukaryotic replicative helicase onto replication origins involves two MCM hexamers forming a double hexamer (DH) around duplex DNA. During S phase, helicase activation requires MCM ...phosphorylation by Dbf4-dependent kinase (DDK), comprising Cdc7 and Dbf4. DDK selectively phosphorylates loaded DHs, but how such fidelity is achieved is unknown. Here, we determine the cryogenic electron microscopy structure of Saccharomyces cerevisiae DDK in the act of phosphorylating a DH. DDK docks onto one MCM ring and phosphorylates the opposed ring. Truncation of the Dbf4 docking domain abrogates DH phosphorylation, yet Cdc7 kinase activity is unaffected. Late origin firing is blocked in response to DNA damage via Dbf4 phosphorylation by the Rad53 checkpoint kinase. DDK phosphorylation by Rad53 impairs DH phosphorylation by blockage of DDK binding to DHs, and also interferes with the Cdc7 active site. Our results explain the structural basis and regulation of the selective phosphorylation of DNA-loaded MCM DHs, which supports bidirectional replication.
SN Ia cosmology depends on the ability to fit and standardize observations of supernova magnitudes with an empirical model. We present here a series of new models of SN Ia spectral time series that ...capture a greater amount of supernova diversity than is possible with the models that are currently customary. These are entitled SuperNova Empirical MOdels (SNEMO; https://snfactory.lbl.gov/snemo). The models are constructed using spectrophotometric time series from 172 individual supernovae from the Nearby Supernova Factory, comprising more than 2000 spectra. Using the available observations, Gaussian processes are used to predict a full spectral time series for each supernova. A matrix is constructed from the spectral time series of all the supernovae, and Expectation Maximization Factor Analysis is used to calculate the principal components of the data. K-fold cross-validation then determines the selection of model parameters and accounts for color variation in the data. Based on this process, the final models are trained on supernovae that have been dereddened using the Fitzpatrick and Massa extinction relation. Three final models are presented here: SNEMO2, a two-component model for comparison with current Type Ia models; SNEMO7, a seven-component model chosen for standardizing supernova magnitudes, which results in a total dispersion of 0.100 mag for a validation set of supernovae, of which 0.087 mag is unexplained (a total dispersion of 0.113 mag with an unexplained dispersion of 0.097 mag is found for the total set of training and validation supernovae); and SNEMO15, a comprehensive 15-component model that maximizes the amount of spectral time-series behavior captured.
Flux is a key measure of the metabolic phenotype. Recently, complete (genome-scale) metabolic network models have been established for Arabidopsis (Arabidopsis thaliana), and flux distributions have ...been predicted using constraints-based modeling and optimization algorithms such as linear programming. While these models are useful for investigating possible flux states under different metabolic scenarios, it is not clear how close the predicted flux distributions are to those occurring in vivo. To address this, fluxes were predicted for heterotrophic Arabidopsis cells and compared with fluxes estimated in parallel by ¹³C-metabolic flux analysis (MFA). Reactions of the central carbon metabolic network (glycolysis, the oxidative pentose phosphate pathway, and the tricarboxylic acid TCA cycle) were independently analyzed by the two approaches. Net fluxes in glycolysis and the TCA cycle were predicted accurately from the genome-scale model, whereas the oxidative pentose phosphate pathway was poorly predicted. MFA showed that increased temperature and hyperosmotic stress, which altered cell growth, also affected the intracellular flux distribution. Under both conditions, the genome-scale model was able to predict both the direction and magnitude of the changes in flux: namely, increased TCA cycle and decreased phosphoenolpyruvate carboxylase flux at high temperature and a general decrease in fluxes under hyperosmotic stress. MFA also revealed a 3-fold reduction in carbon-use efficiency at the higher temperature. It is concluded that constraints-based genome-scale modeling can be used to predict flux changes in central carbon metabolism under stress conditions.
Raffinose family oligosaccharides (RFOs) are implicated in plant regulatory mechanisms of abiotic stresses tolerance and, despite their antinutritional proprieties in grain legumes, little ...information is available about the enzymes involved in RFO metabolism in Fabaceae species. In the present study, the systematic survey of legume proteins belonging to five key enzymes involved in the metabolism of RFOs (galactinol synthase, raffinose synthase, stachyose synthase, alpha-galactosidase, and beta-fructofuranosidase) identified 28 coding-genes in Arachis duranensis and 31 in A. ipaënsis. Their phylogenetic relationships, gene structures, protein domains, and chromosome distribution patterns were also determined. Based on the expression profiling of these genes under water deficit treatments, a galactinol synthase candidate gene (AdGolS3) was identified in A. duranensis. Transgenic Arabidopsis plants overexpressing AdGolS3 exhibited increased levels of raffinose and reduced stress symptoms under drought, osmotic, and salt stresses. Metabolite and expression profiling suggested that AdGolS3 overexpression was associated with fewer metabolic perturbations under drought stress, together with better protection against oxidative damage. Overall, this study enabled the identification of a promising GolS candidate gene for metabolic engineering of sugars to improve abiotic stress tolerance in crops, whilst also contributing to the understanding of RFO metabolism in legume species.
Genome duplication is safeguarded by constantly adjusting the activity of the replicative CMG (CDC45-MCM2-7-GINS) helicase. However, minichromosome maintenance proteins (MCMs)-the structural core of ...the CMG helicase-have never been visualized at sites of DNA synthesis inside a cell (the so-called MCM paradox). Here, we solve this conundrum by showing that anti-MCM antibodies primarily detect inactive MCMs. Upon conversion of inactive MCMs to CMGs, factors that are required for replisome activity bind to the MCM scaffold and block MCM antibody binding sites. Tagging of endogenous MCMs by CRISPR-Cas9 bypasses this steric hindrance and enables MCM visualization at active replisomes. Thus, by defining conditions for detecting the structural core of the replicative CMG helicase, our results explain the MCM paradox, provide visual proof that MCMs are an integral part of active replisomes in vivo, and enable the investigation of replication dynamics in living cells exposed to a constantly changing environment.
We describe catalog-level simulations of Type Ia Supernova (SN Ia) light curves in the Dark Energy Survey Supernova Program (DES-SN), and in low-redshift samples from the Center for Astrophysics ...(CfA) and the Carnegie Supernova Project (CSP). These simulations are used to model biases from selection effects and light curve analysis, and to determine bias corrections for SN Ia distance moduli that are used to measure cosmological parameters. To generate realistic light curves the simulation uses a detailed SN Ia model, incorporates information from observations (PSF, sky noise, zero point), and uses summary information (e.g., detection efficiency vs. signal to noise ratio) based on 10,000 fake SN light curves whose fluxes were overlaid on images and processed with our analysis pipelines. The quality of the simulation is illustrated by predicting distributions observed in the data. Averaging within redshift bins, we find distance modulus biases up to 0.05 mag over the redshift ranges of the low-z and DES-SN samples. For individual events, particularly those with extreme red or blue color, distance biases can reach 0.4 mag. Therefore, accurately determining bias corrections is critical for precision measurements of cosmological parameters. Files used to make these corrections are available at https://des.ncsa.illinois.edu/releases/sn.
IMPORTANCE: Cerebrospinal fluid phosphorylated tau (p-tau) 181, p-tau217, and p-tau231 are associated with neuropathological outcomes, but a comparison of these p-tau isoforms in blood samples is ...needed. OBJECTIVE: To conduct a head-to-head comparison of plasma p-tau181 and p-tau231 measured on the single-molecule array (Simoa) platform and p-tau181 and p-tau217 measured on the Meso Scale Discovery (MSD) platform on amyloid and tau positron emission tomography (PET) measures, neurodegeneration, vascular pathology, and cognitive outcomes. DESIGN, SETTING, AND PARTICIPANTS: This study included data from the Mayo Clinic Study on Aging collected from March 1, 2015, to September 30, 2017, and analyzed between December 15, 2020, and May 17, 2021. Associations between the 4 plasma p-tau measures and dichotomous amyloid PET, metaregion of interest tau PET, and entorhinal cortex tau PET were analyzed using logistic regression models; the predictive accuracy was summarized using area under the receiver operating characteristic curve (AUROC) statistic. Of 1329 participants without dementia and with p-tau181 and p-tau217 on MSD, 200 participants with plasma p-tau181 and p-tau231 on Simoa and magnetic resonance imaging and amyloid and tau PET data at the same study visit were eligible. MAIN OUTCOMES AND MEASURES: Primary outcomes included amyloid (greater than 1.48 standardized uptake value ratio) and tau PET, white matter hyperintensities, white matter microstructural integrity (fractional anisotropy genu of corpus callosum and hippocampal cingulum bundle), and cognition. RESULTS: Of 200 included participants, 101 (50.5%) were male, and the median (interquartile range IQR) age was 79.5 (71.1-84.1) years. A total of 177 were cognitively unimpaired (CU) and 23 had mild cognitive impairment. Compared with amyloid-negative CU participants, among amyloid-positive CU participants, the median (IQR) Simoa p-tau181 measure was 49% higher (2.58 2.00-3.72 vs 1.73 1.45-2.13 pg/mL), MSD p-tau181 measure was 53% higher (1.22 0.91-1.56 vs 0.80 0.66-0.97 pg/mL), MSD p-tau217 measure was 77% higher (0.23 0.17-0.34 vs 0.13 0.09-0.18 pg/mL), and Simoa p-tau231 measure was 49% higher (20.21 15.60-25.41 vs 14.27 11.27-18.10 pg/mL). There were no differences between the p-tau species for amyloid PET and tau PET metaregions of interest. However, among CU participants, both MSD p-tau181 and MSD p-tau217 more accurately predicted abnormal entorhinal cortex tau PET than Simoa p-tau181 (MSD p-tau181: AUROC, 0.80 vs 0.70; P = .046; MSD p-tau217: AUROC, 0.81 vs 0.70; P = .04). MSD p-tau181 and p-tau217 and Simoa p-tau181, but not p-tau231, were associated with greater white matter hyperintensity volume and lower white matter microstructural integrity. CONCLUSIONS AND RELEVANCE: In this largely presymptomatic population, these results suggest subtle differences across plasma p-tau species and platforms for the prediction of amyloid and tau PET and magnetic resonance imaging measures of cerebrovascular and Alzheimer-related pathology.
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