Kinematics signature of a giant planet in the disk of AS 209

[abridged] ALMA observations of dust in protoplanetary disks are revealing the existence of sub-structures such as rings, gaps and cavities. Such morphology are expected to be the outcome of dynamical interaction between the disk and planets. However, other mechanisms are able to produce similar dust sub-structures. A solution is to look at the perturbation induced by the planet to the gas surface density and/or to the kinematics. In the case of the disk around AS 209, a prominent gap has been reported in the surface density of CO at $r \sim 100\,$au. Recently, Bae et al. (2022) detected a localized velocity perturbation in the $^{12}$CO $J=2-1$ emission along with a clump in $^{13}$CO $J=2-1$ at nearly 200 au, interpreted as a gaseous circumplanetary disk. We report a new analysis of ALMA archival observations of $^{12}$CO and $^{13}$CO J=2-1. A clear kinematics perturbation (kink) is detected in multiple channels and over a wide azimuth range in both dataset. We compared the observed perturbation with a semi-analytic model of velocity perturbations due to planet-disk interaction. The observed kink is not consistent with a planet at 200\,au as this would require a low gas disk scale height ($< 0.05$) in contradiction with previous estimate ($h/r \sim 0.118$ at $r = 100$ au). When we fix the disk scale height to 0.118 (at $r = 100$ au) we find instead that a planet of 3-5 M$_{\rm Jup}$ at 100 au induces a kinematics perturbation similar to the observed one. Thus, we conclude that a giant protoplanet orbiting at $r \sim 100\,$au is responsible of the large scale kink as well as of the perturbed dust and gas surface density previously detected. The position angle of the planet is constrained to be between 60$^{\circ}$-100$^{\circ}$. Future observations with high contrast imaging technique in the near- and mid- infrared are needed to confirm the presence and position of such a planet.Comment: Accepted by A&

Papia civitas gloriosa: urban geomorphology for a thematic itinerary on geocultural heritage in Pavia (Central Po Plain, N Italy)

The interaction between geomorphological processes and anthropogenic activities produces an impressive association of geomorphological and archaeological heritage in urban contexts. We analyzed the urban geomorphology and the geo- and cultural heritage in the town of Pavia (N Italy). The city is located in a strategic position, on a series of fluvial terraces where the Romans founded a colony, probably in the place of an Iron Age Gaul settlement. In Medieval Times and the Modern Era, Pavia sprawled outside the Roman walls, creating new urban areas and modifying the landscape. Geomorphological and GIS-spatial analyses integrated with anthropic landform surveying, archaeological data and historical cartography were performed. This multi-disciplinary approach allowed an investigation into how urban development was firstly adapted and then superimposed onto fluvial landforms. As a result, a flexible geocultural itinerary is proposed for linking geoheritage with cultural heritage, and for disseminating urban geomorphology key-concepts

The enhancement of cultural landscapes in mountain environments : an artificial channel history (Torrent-Neuf, Canton Valais, Switzerland) and the role of trees as natural archives of water flow changes

Cultural landscapes represent one of the best examples of the interaction between human and natural environment and cultural trails are an effective way for their valorization. The Torrent-Neuf (Canton Valais, Switzerland) is a cultural trail realized in 2009 along one of the artificial channels used in the region since Medieval times to move water resources from tributary valleys to irrigated lands. Slope instability processes and high maintenance costs provoked the abandonment of the artificial channel in 1934. In 2005 water flow was restored in it. Dendrochronological analyses, carried out on trees growing along the artificial channel banks, allowed collecting information about natural and man-induced hydrological changes, contributing to increase the global value of the whole area

Allergen sensitization is associated with increased dna methylation in older men

Background: Variation in epigenetic modifications, arising from either environmental exposures or internal physiological changes, can influence gene expression and may ultimately contribute to complex diseases such as asthma and allergies. We examined the association of asthma and allergic phenotypes with DNA methylation levels of retrotransposon-derived elements. Methods: We used data from 704 men (mean age 73 years) in the longitudinal Normative Aging Study to assess the relationship between asthma, allergic phenotypes and DNA methylation levels of the retrotransposon-derived elements Alu and long interspersed nuclear element (LINE)-1. Retrotransposons represent a large fraction of the genome (>30%) and are heavily methylated to prevent expression. Percent methylation of Alu and LINE-1 elements in peripheral white blood cells was quantified using PCR pyrosequencing. Data on sensitization to common allergens from skin prick testing, asthma and methacholine responsiveness were gathered approximately 8 years prior to DNA methylation analysis. Results: Prior allergen sensitization was associated with increased methylation of Alu (\u3b2 = 0.32 for sensitized vs. nonsensitized patients; p = 0.003) in models adjusted for pack-years of smoking, body mass index, current smoking, air pollutants, percentage of eosinophils, white blood cell count and age. Of the men interviewed, 5% of subjects reported a diagnosis of asthma. Neither Alu nor LINE-1 methylation was associated with asthma. Conclusions: These data suggest that increased DNA methylation of repetitive elements may be associated with allergen sensitization but does not appear to be associated with asthma. Future work is needed to identify potential underlying mechanisms for these relationships

Placental promoter methylation of DNA repair genes and prenatal exposure to particulate air pollution: an ENVIRONAGE cohort study

BACKGROUND: Exposure to particulate air pollution has been linked with risk of carcinogenesis. Damage to repair pathways might have long-term adverse health effects. We aimed to investigate the association of prenatal exposure to air pollution with placental mutation rate and the DNA methylation of key placental DNA repair genes. METHODS: This cohort study used data from the ongoing ENVironmental Influence ON early AGEing (ENVIRONAGE) birth cohort, which enrols pairs of mothers and neonates (singleton births only) at the East-Limburg Hospital (Genk, Belgium). Placental DNA samples were collected after birth. We used bisulfite-PCR-pyrosequencing to investigate the mutation rate of Alu (a marker for overall DNA mutation) and DNA methylation in the promoter genes of key DNA repair and tumour suppressor genes (APEX1, OGG1, PARP1, ERCC1, ERCC4, p53, and DAPK1). We used a high-resolution air pollution model to estimate exposure to particulate matter with a diameter less than 2·5 μm (PM2·5), black carbon, and NO2 over the entire pregnancy on the basis of maternal address. Alu mutation was analysed with a linear regression model, and methylation values of the selected genes were analysed in mixed-effects models. Effect estimates are presented as the relative percentage change in methylation for an ambient air pollution increment of one IQR (ie, the difference between the first and third quartiles of exposure in the entire cohort). FINDINGS: 500 biobanked placental DNA samples were randomly selected from 814 pairs of mothers and neonates who were recruited to the cohort between Feb 1, 2010, and Dec 31, 2014, of which 463 samples met the pyrosequencing quality control criteria. IQR exposure increments were 3·84 μg/m3 for PM2·5, 0·36 μg/m3 for black carbon, and 5·34 μg/m3 for NO2. Among these samples, increased Alu mutation rate was associated with greater exposure to PM2·5 (r=0·26, p<0·0001) and black carbon (r=0·33, p<0·0001), but not NO2. Promoter methylation was positively associated with PM2·5 in APEX1 (7·34%, 95% CI 0·52 to 14·16, p=0·009), OGG1 (13·06, 3·88 to 22·24, p=0·005), ERCC4 (16·31%, 5·43 to 27·18, p=0·01), and p53 (10·60%, 4·46 to 16·74, p=0·01), whereas promoter methylation of DAPK1 (-12·92%, -22·35 to -3·49, p=0·007) was inversely associated with PM2·5 exposure. Black carbon exposure was associated with elevated promoter methylation in APEX1 (9·16%, 4·06 to 14·25, p=0·01) and ERCC4 (27·56%, 17·58 to 37·55, p<0·0001). Promoter methylation was not associated with pollutant exposure in PARP1 and ERCC1, and NO2 exposure was not associated with methylation in any of the genes studied. INTERPRETATION: Transplacental in-utero exposure to particulate matter is associated with an increased overall placental mutation rate (as measured with Alu), which occurred in concert with epigenetic alterations in key DNA repair and tumour suppressor genes. Our results suggest that exposure to air pollution can induce changes to fetal and neonatal DNA repair capacity. Future studies will be essential to elucidate whether these changes persist and have a role in carcinogenic insults later in life. The work is supported by the European Research Council (ERC-2012-StG.310898 and ERC-2011-StG. 282413) and by the Flemish Scientific Fund (FWO,G073315N/G082317N)

Use and misuse of multivariable approaches in interventional cardiology studies on drug-eluting stents: a systematic review.

Aims: Randomized clinical trials (RCTs) are the most reliable evidence, even if they require important resource and logistic efforts. Large, cost-free and real-world datasets may be easily accessed yielding to observational studies, but such analyses often lead to problematic results in the absence of careful methods, especially from a statistic point of view. We aimed to appraise the performance of current multivariable approaches in the estimation of causal treatment and effects in studies focusing on drug-eluting stents (DES). Methods and Results: Pertinent studies published in the literature were searched, selected, abstracted, and appraised for quality and validity features. Six studies with a logistic regression were included, all of them reporting more than 10 events for covariates and different length of follow-up, with an overall low risk of bias. Most of the 15 studies with a Cox proportional hazard analysis had a different follow-up, with less than 10 events for covariates, yielding an overall low or moderate risk of bias. Sixteen studies with propensity score were included: the most frequent method for variable selection was logistic regression, with underlying differences in follow-up and less than 10 events for covariate in most of them. Most frequently, calibration appraisal was not reported in the studies, on the contrary of discrimination appraisal, which was more frequently performed. In seventeen studies with propensity and matching, the latter was most commonly performed with a nearest neighbor-matching algorithm yet without appraisal in most of the studies of calibration or discrimination. Balance was evaluated in 46% of the studies, being obtained for all variables in 48% of them. Conclusions: Better exploitation and methodological appraisal of multivariable analysis is needed to improve the clinical and research impact and reliability of nonrandomized studies. (J Interven Cardiol 2012;**:1-1

Lupin Peptide T9 (GQEQSHQDEGVIVR) Modulates the Mutant PCSK9D374Y Pathway : in vitro Characterization of its Dual Hypocholesterolemic Behavior

GQEQSHQDEGVIVR (T9) is a peptide originated by the tryptic digestion of lupin \u3b2-conglutin that is absorbed in human intestinal Caco-2 cells. A previous study has shown that T9 impairs the protein-protein interaction between mutant D374Y Proprotein Convertase Subtilisin/Kexin 9 (PCSK9D374Y) and the low-density lipoprotein receptor (LDLR), thus exerting a hypocholesterolemic effect. Moreover, a bioinformatic study predicting that T9 may potentially act as an inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCoAR), has suggested a complementary cholesterol-lowering activity. The present study demonstrates that T9 inhibits in vitro the HMGCoAR functionality with an IC50 value of 99.5 \ub1 0.56 \ub5M. Through the inhibition of either HMGCoAR or PCSK9D374Y activities, T9 enhances the LDLR protein levels leading to an improved ability of HepG2 cells transfected with the mutant PCSK9D374Y-FLAG plasmid to uptake extracellular LDL with a final cholesterol-lowering effect. In addition, T9 modulates the PCSK9D374Y signaling pathway in transfected HepG2 cells leading to a decrease of PCSK9D374Y and HNF-1\u3b1 protein levels. All these results indicate that the hypocholesterolemic effects of T9 are due to a dual mechanism of action involving either the modulation of the PCSK9D374Y or LDLR pathways. This may represent an added value from a therapeutic point of view

Repetitive element hypomethylation in blood leukocyte DNA and cancer incidence, prevalence, and mortality in elderly individuals : the Normative Aging Study

BACKGROUND: Global genomic hypomethylation is a common epigenetic event in cancer that mostly results from hypomethylation of repetitive DNA elements. Case-control studies have associated blood leukocyte DNA hypomethylation with several cancers. Because samples in case-control studies are collected after disease development, whether DNA hypomethylation is causal or just associated with cancer development is still unclear. METHODS: In 722 elderly subjects from the Normative Aging Study cohort, we examined whether DNA methylation in repetitive elements (Alu, LINE-1) was associated with cancer incidence (30 new cases, median follow-up: 89 months), prevalence (205 baseline cases), and mortality (28 deaths, median follow-up: 85 months). DNA methylation was measured by bisulfite pyrosequencing. RESULTS: Individuals with low LINE-1 methylation (<median) had a 3.0-fold (95%CI 1.3-6.9) increased incidence of all cancers combined. LINE-1 and Alu methylation were not significantly associated with cancer prevalence at baseline (all cancers combined). However, individuals with low LINE-1 methylation (<median) had a 3.2-fold (95% CI 1.4-7.5) higher prevalence of lung cancer. Individuals with low LINE-1 or Alu methylation (<median) had increased cancer mortality (HR = 3.2, 95%CI 1.3-7.9 for LINE-1; HR = 2.5, 95%CI 1.1-5.8 for Alu). CONCLUSION: These findings suggest that individuals with lower repetitive element methylation are at high risk of developing and dying from cancer

Identification of RNA polymerase III-transcribed Alu loci by computational screening of RNA-Seq data

Of the 3c1.3 million Alu elements in the human genome, only a tiny number are estimated to be active in transcription by RNA polymerase (Pol) III. Tracing the individual loci from which Alu transcripts originate is complicated by their highly repetitive nature. By exploiting RNA-Seq data sets and unique Alu DNA sequences, we devised a bioinformatic pipeline allowing us to identify Pol III-dependent transcripts of individual Alu elements. When applied to ENCODE transcriptomes of seven human cell lines, this search strategy identified 3c1300 Alu loci corresponding to detectable transcripts, with 3c120 of them expressed in at least three cell lines. In vitro transcription of selected Alus did not reflect their in vivo expression properties, and required the native 5'-flanking region in addition to internal promoter. We also identified a cluster of expressed AluYa5-derived transcription units, juxtaposed to snaR genes on chromosome 19, formed by a promoter-containing left monomer fused to an Alu-unrelated downstream moiety. Autonomous Pol III transcription was also revealed for Alus nested within Pol II-transcribed genes. The ability to investigate Alu transcriptomes at single-locus resolution will facilitate both the identification of novel biologically relevant Alu RNAs and the assessment of Alu expression alteration under pathological conditions