methylKit: a comprehensive R package for the analysis of genome-wide DNA methylation profiles

DNA methylation is a chemical modification of cytosine bases that is pivotal for gene regulation, cellular specification and cancer development. Here, we describe an R package, methylKit, that rapidly analyzes genome-wide cytosine epigenetic profiles from high-throughput methylation and hydroxymethylation sequencing experiments. methylKit includes functions for clustering, sample quality visualization, differential methylation analysis and annotation features, thus automating and simplifying many of the steps for discerning statistically significant bases or regions of DNA methylation. Finally, we demonstrate methylKit on breast cancer data, in which we find statistically significant regions of differential methylation and stratify tumor subtypes. methylKit is available at http://code.google.com/p/methylkit

Free Volatile Compounds of cv. Pedro Giménez (Vitis vinifera L.) White Grape Must Grown in San Juan, Argentina

The free aromatic composition of must from Pedro Giménez grapes, grown in San Juan, Argentina, was characterised. Samples from the vintages of 2008 and 2009 were analysed by gas chromatography–mass spectrometry–solid phase microextraction (GC–MS–SPME). Higher alcohols, terpenes, C13-norisoprenoids, esters, aldehydes and ketones were quantified. The calculation of the odour activity values (OAVs) revealed that β-damascenone, α-ionone, β-linalool, geraniol, ethyl butanoate, hexanoate and octanoate were the most prevalent aroma-active compounds of the grape variety. However, the remaining 42 aromatic compounds that registered OAVs less than 1 could potentially contribute to the flavour of Pedro Giménez grapes. The measured monoterpene levels indicate that the Pedro Giménez grape can be considered a neutral variety.  This is the first report describing the main potential free aroma contributors of Pedro Giménez grapes in two consecutive years

Las anomalías precoces de la continuidad en el discurso constituyen biomarcadores predictivos de psicosis

Language is being systematized as an area of clinical research because it contains features that function as a biomarker for the prediction of psychosis. The aim of the study was to contrast two types of continuity features such as connection, iteration, and referential distance, and, on the other hand, those of verbal fluency, understood as the presence of aberrant pauses. Clinical interviews of 10 patients diagnosed with schizophrenia, 10 CHR and 10 healthy controls were analyzed. For the analysis of referentiality, sentence windows were selected and for verbal fluency, 15 minutes of speech were considered. The results suggest the presence of abnormalities in referentiality and verbal fluency among the CHR population. These similarities are found in terms of occurrence and similarity to those of the schizophrenia group, which supports our hypothesis that they are predictive biomarkers.El lenguaje se está sistematizando como área de pesquisa clínica porque contiene características que funcionan como un biomarcador para la predicción de psicosis. El objetivo del estudio fue contrastar dos tipos de características de continuidad discursiva entre personas que cursan Estados Mentales de Alto Riesgo (CHR) y personas con diagnóstico de esquizofrenia. Nos referimos, por una parte, a características referenciales, tales como conexión, iteración y distancia referencial, y, por otra, a las de fluidez verbal, entendida como la presencia de pausas aberrantes. Se analizaron entrevistas clínicas de 10 pacientes diagnosticados de esquizofrenia, 10 CHR y 10 controles sanos. Para el análisis de la referencialidad se seleccionaron ventanas de oraciones y para la fluidez verbal se consideraron 15 minutos de habla. Los resultados apuntan a que existe presencia de anomalías en referencialidad y en fluidez verbal entre la población CHR. Dichas similitudes se dan en cuanto a ocurrencia y similitud respecto a las del grupo con esquizofrenia, lo que refrenda nuestra hipótesis de que constituyen biomarcadores predictivos.  

Superization of Homogeneous Spin Manifolds and Geometry of Homogeneous Supermanifolds

Let M_0=G_0/H be a (pseudo)-Riemannian homogeneous spin manifold, with reductive decomposition g_0=h+m and let S(M_0) be the spin bundle defined by the spin representation Ad:H->\GL_R(S) of the stabilizer H. This article studies the superizations of M_0, i.e. its extensions to a homogeneous supermanifold M=G/H whose sheaf of superfunctions is isomorphic to Lambda(S^*(M_0)). Here G is the Lie supergroup associated with a certain extension of the Lie algebra of symmetry g_0 to an algebra of supersymmetry g=g_0+g_1=g_0+S via the Kostant-Koszul construction. Each algebra of supersymmetry naturally determines a flat connection nabla^{S} in the spin bundle S(M_0). Killing vectors together with generalized Killing spinors (i.e. nabla^{S}-parallel spinors) are interpreted as the values of appropriate geometric symmetries of M, namely even and odd Killing fields. An explicit formula for the Killing representation of the algebra of supersymmetry is obtained, generalizing some results of Koszul. The generalized spin connection nabla^{S} defines a superconnection on M, via the super-version of a theorem of Wang.Comment: 50 page

Role of targeted therapies in rheumatic patients on COVID-19 outcomes: Results from the COVIDSER study

Objectives To analyse the effect of targeted therapies, either biological (b) disease-modifying antirheumatic drugs (DMARDs), targeted synthetic (ts) DMARDs and other factors (demographics, comorbidities or COVID-19 symptoms) on the risk of COVID-19 related hospitalisation in patients with inflammatory rheumatic diseases. Methods The COVIDSER study is an observational cohort including 7782 patients with inflammatory rheumatic diseases. Multivariable logistic regression was used to estimate ORs and 95% CIs of hospitalisation. Antirheumatic medication taken immediately prior to infection, demographic characteristics, rheumatic disease diagnosis, comorbidities and COVID-19 symptoms were analysed. Results A total of 426 cases of symptomatic COVID-19 from 1 March 2020 to 13 April 2021 were included in the analyses: 106 (24.9%) were hospitalised and 19 (4.4%) died. In multivariate-adjusted models, bDMARDs and tsDMARDs in combination were not associated with hospitalisation compared with conventional synthetic DMARDs (OR 0.55, 95% CI 0.24 to 1.25 of b/tsDMARDs, p=0.15). Tumour necrosis factor inhibitors (TNF-i) were associated with a reduced likelihood of hospitalisation (OR 0.32, 95% CI 0.12 to 0.82, p=0.018), whereas rituximab showed a tendency to an increased risk of hospitalisation (OR 4.85, 95% CI 0.86 to 27.2). Glucocorticoid use was not associated with hospitalisation (OR 1.69, 95% CI 0.81 to 3.55). A mix of sociodemographic factors, comorbidities and COVID-19 symptoms contribute to patients'' hospitalisation. Conclusions The use of targeted therapies as a group is not associated with COVID-19 severity, except for rituximab, which shows a trend towards an increased risk of hospitalisation, while TNF-i was associated with decreased odds of hospitalisation in patients with rheumatic disease. Other factors like age, male gender, comorbidities and COVID-19 symptoms do play a role.

Heterogeneity of luminal breast cancer characterised by immunohistochemical expression of basal markers

Background: Luminal A breast cancer defined as hormone receptor positive and human epidermal growth factor receptor 2 (HER2) negative is known to be heterogeneous. Previous study showed that luminal A tumours with the expression of basal markers ((cytokeratin (CK) 5 or CK5/6) or epidermal growth factor receptor (EGFR)) were associated with poorer prognosis compared with those that stained negative for basal markers. Prompted by this study, we assessed whether tumour characteristics and risk factors differed by basal marker status within luminal A tumours. Methods: We pooled 5040 luminal A cases defined by immunohistochemistry (4490 basal-negative ((CK5 (or CK5/6))− and EGFR−) and 550 basal-positive ((CK5 (or CK5/6+)) or EGFR+)) from eight studies participating in the Breast Cancer Association Consortium. Case–case comparison was performed using unconditional logistic regression. Results: Tumour characteristics and risk factors did not vary significantly by the expression of basal markers, although results suggested that basal-positive luminal tumours tended to be smaller and node negative, and were more common in women with a positive family history and lower body mass index. Conclusions: Most established breast cancer risk factors were similar in basal-positive and basal-negative luminal A tumours. The non-significant but suggestive differences in tumour features and family history warrant further investigations

Phase I clinical trial in healthy adults of a nasal vaccine candidate containing recombinant hepatitis B surface and core antigens

SummaryBackgroundThe nasal vaccine candidate (NASVAC), comprising hepatitis B virus (HBV) surface (HBsAg) and core antigens (HBcAg), has been shown to be highly immunogenic in animal models.MethodsA phase I double-blinded, placebo-controlled randomized clinical trial was carried out in 19 healthy male adults with no serologic markers of immunity/infection to HBV. This study was aimed at exploring the safety and immunogenic profile of nasal co-administration of both HBV recombinant antigens. The trial was performed according to Good Clinical Practice guidelines. Participants ranged in age from 18 to 45 years and were randomly allocated to receive a mixture of 50μg HBsAg and 50μg HBcAg or 0.9% physiologic saline solution, as a placebo, via nasal spray in a five-dose schedule at 0, 7, 15, 30, and 60 days. A total volume of 0.5ml was administered in two dosages of 125μl per nostril. Adverse events were actively recorded 1h, 6h, 12h, 24h, 48h, 72h, 7 days and 30 days after each dose. Anti-HBs and anti-HBc titers were evaluated using corresponding ELISA kits at days 30 and 90.ResultsThe vaccine candidate was safe and well tolerated. Adverse reactions included sneezing (34.1%), rhinorrhea (12.2%), nasal stuffiness (9.8%), palate itching (9.8%), headache (9.8%), and general malaise (7.3%). These reactions were all self-limiting and mild in intensity. No severe or unexpected events were recorded during the trial. The vaccine elicited anti-HBc seroconversion in 100% of subjects as early as day 30 of the immunization schedule, while a seroprotective anti-HBs titer (≥10IU/l) was at a maximum at day 90 (75%). All subjects in the placebo group remained seronegative during the trial.ConclusionThe HBsAg–HBcAg vaccine candidate was safe, well tolerated and immunogenic in this phase I study in healthy adults. To our knowledge, this is the first demonstration of safety and immunogenicity for a nasal vaccine candidate comprising HBV antigens

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

The First Millennium-Age Araucaria Araucana in Patagonia

This item is part of the Tree-Ring Research (formerly Tree-Ring Bulletin) archive. For more information about this peer-reviewed scholarly journal, please email the Editor of Tree-Ring Research at [email protected]

High-throughput automated scoring of Ki67 in breast cancer tissue microarrays from the Breast Cancer Association Consortium (BCAC)

Automated methods are needed to facilitate high-throughput and reproducible scoring of Ki67 and other markers in breast cancer tissue microarrays (TMAs) in large-scale studies. To address this need, we developed an automated protocol for Ki67 scoring and evaluated its performanc